ORCID Profile
0000-0002-7102-2413
Current Organisation
Garvan Institute of Medical Research
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Publisher: Wiley
Date: 03-2009
DOI: 10.1359/JBMR.081104
Abstract: Multiple myeloma (MM) is associated with the development of osteolytic bone disease, mediated by increased osteoclastic bone resorption and impaired osteoblastic bone formation. Dickkopf-1 (Dkk1), a soluble inhibitor of wingless/int (Wnt) signaling and osteoblastogenesis, is elevated in patients with MM and correlates with osteolytic bone disease. In this study, we investigated the effect of inhibiting Dkk1 on the development of osteolytic lesions in the 5T2MM murine model of myeloma. We showed that Dkk1 is expressed by murine 5T2MM myeloma cells. Injection of 5T2MM cells into C57BL/KaLwRij mice resulted in the development of osteolytic bone lesions (p < 0.05), mediated by increased osteoclast numbers (p < 0.001) and a decrease in osteoblast numbers (p < 0.001) and mineralizing surface (p < 0.05). Mice bearing 5T2MM cells were treated with an anti-Dkk1 antibody (BHQ880, 10 mg/kg, IV, twice weekly for 4 wk) from time of paraprotein detection. Anti-Dkk1 treatment prevented 5T2MM-induced suppression of osteoblast numbers (p < 0.001) and surface (p < 0.001). Treatment increased mineralizing surface by 28% and bone formation rate by 25% however, there was no change in mineral apposition rate. Inhibiting Dkk1 had no effect on osteoclast numbers. muCT analysis showed that anti-Dkk1 treatment significantly protected against 5T2MM-induced trabecular bone loss (p < 0.05) and reduced the development of osteolytic bone lesions (p < 0.05). Treatment had no significant effect on tumor burden. These data suggest that inhibiting Dkk1 prevents the suppression of bone formation and in doing so is effective in preventing the development of osteolytic bone disease in myeloma, offering an effective therapeutic approach to treating this clinically important aspect of myeloma.
Publisher: Portland Press Ltd.
Date: 04-1992
DOI: 10.1042/CS0820429
Abstract: 1. Total body areal bone mineral density was measured by dual-energy X-ray absorptiometry in eight women before and 10 weeks after a very-low-calorie diet [405 kcal (1701 kJ)/day]. 2. The mean weight loss of 15.6 kg was accompanied by a statistically significant reduction in total body bone mineral density from 1.205 ± 0.056 to 1.175 ± 0.058 g/cm2 (mean ± sd, P & 0.005). 3. After cessation of the diet, weight gradually increased and by 10 months was similar to baseline values. Total body bone mineral density also increased after stopping the diet and mean values obtained 10 months after the diet did not differ significantly from initial values. Throughout the study total body bone mineral density values in all subjects were well within the range reported for normal subjects. 4. These data indicate that diet-induced weight loss is associated with rapid bone loss, subsequent weight gain being accompanied by increases in bone mass. Further studies are required to establish the clinical significance of these findings and, in particular, the skeletal distribution of bone loss.
Publisher: The Endocrine Society
Date: 03-2014
DOI: 10.1210/EN.2013-1247
Publisher: Public Library of Science (PLoS)
Date: 28-12-2020
DOI: 10.1371/JOURNAL.PGEN.1009190
Abstract: The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease.
Publisher: Wiley
Date: 23-01-2003
DOI: 10.1002/CNCR.11125
Abstract: A major clinical feature in multiple myeloma is the development of osteolytic bone disease. The increase in bone destruction is due to uncontrolled osteoclastic bone resorption. Until recently the factors responsible for mediating the increase in osteoclast formation in myeloma have been unclear. However, recent studies have implicated a number of factors, including the ligand for receptor activator of NFkappaB (RANKL) and macrophage inflammatory protein-1alpha. The demonstration that increased osteoclastic activity plays a central role in this process and the identification of molecules that may play a critical role in the development of myeloma bone disease have resulted in studies aimed at identifying new approaches to treating this aspect of myeloma. Studies have been performed to determine the ability of recombinant osteoprotegerin (Fc.OPG), a soluble decoy receptor for RANKL, and potent new bisphosphonates to inhibit the development of myeloma bone disease in the 5T2MM murine model of multiple myeloma. Fc.OPG was shown to prevent the development of osteolytic bone lesions in 5T2MM bearing animals. These changes were associated with a preservation of the cancellous bone loss induced by myeloma cells and an inhibition of osteoclast formation. Bisphosphonates, including ibandronate and zoledronic acid, were also shown to inhibit the development of osteolytic bone lesions in the 5T2MM model and alternative models of myeloma bone disease. Bisphosphonates and Fc.OPG are effective inhibitors of the development of osteolytic bone lesions in pre-clinical murine models of myeloma bone disease.
Publisher: Elsevier BV
Date: 2001
Publisher: Springer Science and Business Media LLC
Date: 04-06-2009
DOI: 10.1038/LEU.2009.121
Abstract: Multiple myeloma (MM) is a B-cell malignancy, which often remains incurable because of the development of drug resistance governed by the bone marrow (BM) microenvironment. Novel treatment strategies are therefore urgently needed. In this study, we evaluated the anti-MM activity of JNJ-26481585, a novel 'second-generation' pyrimidyl-hydroxamic acid-based histone deacetylase inhibitor, using the syngeneic murine 5TMM model of MM. In vitro, JNJ-26481585 induced caspase cascade activation and upregulation of p21, resulting in apoptosis and cell cycle arrest in the myeloma cells at low nanomolar concentrations. Similar results could be observed in BM endothelial cells using higher concentrations, indicating the selectivity of JNJ-26481585 toward cancer cells. In a prophylactic and therapeutic setting, treatment with JNJ-26481585 resulted in an almost complete reduction of the tumor load and a significant decrease in angiogenesis. 5T2MM-bearing mice also developed a MM-related bone disease, characterized by increased osteoclast number, development of osteolytic lesions and a reduction in cancellous bone. Treatment of these mice with JNJ-264815 significantly reduced the development of bone disease. These data suggest that JNJ-26481585 has a potent anti-MM activity that can overcome the stimulatory effect of the BM microenvironment in vivo making this drug a promising new anti-MM agent.
Publisher: Springer Science and Business Media LLC
Date: 12-2008
DOI: 10.1038/LEU.2008.288
Publisher: Springer Science and Business Media LLC
Date: 20-10-2015
Publisher: Informa UK Limited
Date: 1998
DOI: 10.3109/10428199809059253
Abstract: Multiple myeloma is a haematological malignancy characterized by an expansion of malignant plasma cells within the bone marrow and is frequently associated with bone disease involving the development of osteolytic bone lesions, pathological fractures, osteoporosis and hypercalcaemia. A class of anti-resorptive drugs known as bisphosphonates have been in use to treat osteoclast-mediated bone diseases for the past 3 decades, and are currently proving effective in the treatment of the bone disease associated with multiple myeloma. Recent studies have suggested that bisphosphonate treatment may also result in an improvement in survival in some patients with multiple myeloma. These effects on survival may reflect an indirect effect of the bisphosphonates on tumour growth, via inhibition of osteoclast activity and hence a reduction in the release of tumour growth factors. However, it is also possible that bisphosphonates may have a direct effect on myeloma cells. In support of this we have demonstrated that bisphosphonates can decrease cell proliferation and induce apoptosis in human myeloma cells in vitro, and this review discusses the possibility that bisphosphonates may have not only an anti-resorptive action, but may also have a direct anti-tumour activity.
Publisher: Wiley
Date: 14-05-2009
DOI: 10.1002/IJC.24436
Abstract: Prostate, breast and lung cancers readily develop bone metastases which lead to fractures, hypercalcemia and pain. Malignant growth in the bones depends on osteoclast-mediated bone resorption and in this regard bisphosphonate compounds, which have high-bone affinity and inhibit osteoclast activity, have been found to alleviate bone cancer symptoms. In this study, the bisphosphonate risedronate and its phosphonocarboxylate derivative NE-10790 was tested in a murine bone cancer pain model. Risedronate decreased bone cancer-related bone destruction and pain-related behavior and decreased the spinal expression of glial fibrillary acidic protein, whereas NE-10790 had no effect on these parameters. Furthermore, risedronate but not NE-10790 induced dose-dependent toxicity in NCTC-2472 cells in vitro. Furthermore, the direct toxic effect of risedronate on tumor cells observed in vitro opens the possibility that a direct toxic effect on tumor cells may also be present in vivo and be related to the efficacy of bisphosphonate compounds. In conclusion, these results suggest that risedronate treatment may lead to an increased life quality, in patient suffering from bone cancer, in terms of decreased osteolysis and pain, and merits further study.
Publisher: Springer Science and Business Media LLC
Date: 09-1993
DOI: 10.1007/BF01623826
Publisher: Impact Journals, LLC
Date: 03-2017
Publisher: BMJ
Date: 06-1989
DOI: 10.1136/ARD.48.6.483
Abstract: The cellular basis of trabecular bone loss in rheumatoid arthritis was investigated in 45 non-steroid treated patients. Mean wall thickness, an indicator of the amount of bone formed per remodelling unit, mean interstitial bone thickness, which is related to resorption depth, and the extent of trabecular surface covered by osteoid, which reflects the number of remodelling units, were assessed in iliac crest biopsy specimens. The mean wall thickness was significantly reduced in the patient group when compared with controls matched for age and sex (mean (SD) 39.8 (5.4) v 51.6 (9.7) microns). There was no significant difference between patients and controls in the mean interstitial bone thickness (51.0 (26.4) v 61.4 (31.9) microns) or osteoid surface (16.7 (11.4) v 21.0 (10.5)%). These results show that reduced bone formation at the remodelling unit level is the predominant mechanism of bone loss in rheumatoid arthritis.
Publisher: Wiley
Date: 22-01-2009
DOI: 10.1002/DVDY.21838
Abstract: The transcription factors RUNX2 and OSX have been shown to act sequentially to direct mammalian osteoblast differentiation. RUNX2 is required during the early stages of commitment and acts in part to activate Osx transcription. OSX and RUNX2 then act to direct transcription of bone matrix proteins. Here, we investigate the expression of these genes and others during zebrafish osteoblastogenesis. Using whole-mount in situ hybridization, we find that, during the formation of a given bone, the zebrafish homologues of mouse Runx2 (runx2a and runx2b) are typically expressed before the onset of osx. osx expression is usually followed by up-regulation of the bone matrix proteins, col1a2 and osteonectin. These results suggest that the mammalian pathway is conserved during development of the head and shoulder skeleton of zebrafish. We also analyze the expression of three atypical bone markers (tcf7, cvl2, and col10a1) in an effort to place them within this canonical hierarchy.
Publisher: Wiley
Date: 25-05-2023
DOI: 10.1002/JBMR.4809
Abstract: An imbalance between bone resorption and bone formation underlies the devastating osteolytic lesions and subsequent fractures seen in more than 90% of multiple myeloma (MM) patients. Currently, Wnt‐targeted therapeutic agents that prevent soluble antagonists of the Wnt signaling pathway, sclerostin (SOST) and dickkopf‐1 (DKK1), have been shown to prevent bone loss and improve bone strength in preclinical models of MM. In this study, we show increasing Wnt signaling via a novel anti–low‐density lipoprotein receptor‐related protein 6 (LRP6) antibody, which potentiates Wnt1‐class ligand signaling through binding the Wnt receptor LRP6, prevented the development of myeloma‐induced bone loss primarily through preventing bone resorption. When combined with an agent targeting the soluble Wnt antagonist DKK1, we showed more robust improvements in bone structure than anti‐LRP6 treatment alone. Micro–computed tomography (μCT) analysis demonstrated substantial increases in trabecular bone volume in naïve mice given the anti‐LRP6/DKK1 combination treatment strategy compared to control agents. Mice injected with 5TGM1eGFP murine myeloma cells had significant reductions in trabecular bone volume compared to naïve controls. The anti‐LRP6/DKK1 combination strategy significantly improved bone volume in 5TGM1‐bearing mice by 111%, which was also superior to anti‐LRP6 single treatment with similar bone structural changes observed within L 4 lumbar vertebrae. Consequently, this combination strategy significantly improved resistance to fracture in lumbar vertebrae in 5TGM1‐bearing mice compared to their controls, providing greater protection against fracture compared to anti‐LRP6 antibody alone. Interestingly, these improvements in bone volume were primarily due to reduced bone resorption, with significant reductions in osteoclast numbers and osteoclast surface per bone surface demonstrated in 5TGM1‐bearing mice treated with the anti‐LRP6/DKK1 combination strategy. Importantly, Wnt stimulation with either single or combined Wnt‐targeted agents did not exacerbate tumor activity. This work provides a novel approach of targeting both membrane‐bound and soluble Wnt pathway components to provide superior skeletal outcomes in patients with multiple myeloma and other bone destructive cancers. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Publisher: Wiley
Date: 20-03-2012
DOI: 10.1002/JBMR.1495
Abstract: Bone diseases such as rickets and osteoporosis cause significant reduction in bone quantity and quality, which leads to mechanical abnormalities. However, the precise ultrastructural mechanism by which altered bone quality affects mechanical properties is not clearly understood. Here we demonstrate the functional link between altered bone quality (reduced mineralization) and abnormal fibrillar-level mechanics using a novel, real-time synchrotron X-ray nanomechanical imaging method to study a mouse model with rickets due to reduced extrafibrillar mineralization. A previously unreported N-ethyl-N-nitrosourea (ENU) mouse model for hypophosphatemic rickets (Hpr), as a result of missense Trp314Arg mutation of the phosphate regulating gene with homologies to endopeptidase on the X chromosome (Phex) and with features consistent with X-linked hypophosphatemic rickets (XLHR) in man, was investigated using in situ synchrotron small angle X-ray scattering to measure real-time changes in axial periodicity of the nanoscale mineralized fibrils in bone during tensile loading. These determine nanomechanical parameters including fibril elastic modulus and maximum fibril strain. Mineral content was estimated using backscattered electron imaging. A significant reduction of effective fibril modulus and enhancement of maximum fibril strain was found in Hpr mice. Effective fibril modulus and maximum fibril strain in the elastic region increased consistently with age in Hpr and wild-type mice. However, the mean mineral content was ∼21% lower in Hpr mice and was more heterogeneous in its distribution. Our results are consistent with a nanostructural mechanism in which incompletely mineralized fibrils show greater extensibility and lower stiffness, leading to macroscopic outcomes such as greater bone flexibility. Our study demonstrates the value of in situ X-ray nanomechanical imaging in linking the alterations in bone nanostructure to nanoscale mechanical deterioration in a metabolic bone disease.
Publisher: The American Association of Immunologists
Date: 15-03-2007
DOI: 10.4049/JIMMUNOL.178.6.3379
Abstract: Apoptosis through Fas/Fas ligand (FasL) is an important regulator of immune system homeostasis but its role in bone homeostasis is elusive. We systematically analyzed: 1) the expression of Fas/FasL during osteoblastogenesis and osteoclastogenesis in vitro, 2) the effect of FasL on apoptosis and osteoblastic/osteoclastic differentiation, and 3) osteoblastogenesis and osteoclastogenesis in mice deficient in Fas or FasL. The expression of Fas increased with osteoblastic differentiation. Addition of FasL weakly increased the proportion of apoptotic cells in both osteoclastogenic and osteoblastogenic cultures. In a CFU assay, FasL decreased the proportion of osteoblast colonies but did not affect the total number of colonies, indicating specific inhibitory effect of Fas/FasL on osteoblastic differentiation. The effect depended on the activation of caspase 8 and was specific, as addition of FasL to osteoblastogenic cultures significantly decreased gene expression for runt-related transcription factor 2 (Runx2) required for osteoblastic differentiation. Bone marrow from mice without functional Fas or FasL had similar osteoclastogenic potential as bone marrow from wild-type mice, but generated more osteoblast colonies ex vivo. These colonies had increased expression of the osteoblast genes Runx2, osteopontin, alkaline phosphatase, bone sialoprotein, osteocalcin, and osteoprotegerin. Our results indicate that Fas/FasL system primarily controls osteoblastic differentiation by inhibiting progenitor differentiation and not by inducing apoptosis. During osteoclastogenesis, the Fas/FasL system may have a limited effect on osteoclast progenitor apoptosis. The study suggests that Fas/FasL system plays a key role in osteoblastic differentiation and provides novel insight into the interactions between the immune system and bone.
Publisher: Springer Science and Business Media LLC
Date: 2001
Publisher: Wiley
Date: 08-2001
DOI: 10.1046/J.1365-2141.2001.02963.X
Abstract: Syndecan-1 is a cell surface proteoglycan that is expressed on human myeloma cells and is thought to act as a co-receptor for certain extracellular matrix proteins and growth factors. The ectodomain of syndecan-1 is thought to be shed from the surface of myeloma cells, although the exact mechanism of release remains unclear. In this study, we used a panel of inhibitors to identify the class of proteinase responsible for shedding the soluble syndecan-1 ectodomain from human myeloma cells. Using enzyme-linked immunosorbent assay, flow cytometry and immunocytochemistry, we demonstrated that myeloma cell lines expressed syndecan-1 on their surface and that this was shed constitutively, but to a varying extent. In addition, phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C, stimulated a marked loss of cell surface syndecan-1 from each of the cell lines and this was associated with a corresponding increase in soluble syndecan-1. Inhibitors of serine and cysteine proteinases, and matrix-type metalloproteinases, did not inhibit constitutive or PMA-stimulated syndecan-1 shedding from JJN3 and RPMI 8226 cells. However, BB-94, a hydroxamate-based, broad-spectrum, metalloproteinase inhibitor, substantially suppressed constitutive and PMA-stimulated syndecan-1 loss from myeloma cells. These data indicate that a non-matrix-type metalloproteinase is responsible for syndecan-1 shedding from the surface of myeloma cells.
Publisher: Humana Press
Date: 2005
DOI: 10.1385/1-59259-916-8:191
Abstract: Multiple myeloma is a B-cell neoplasm characterized by the monoclonal proliferation of plasma cells in the bone marrow, the development of osteolytic lesions, and the induction of angiogenesis. These different processes require three-dimensional interactions, with both humoral and cellular contacts. The 5TMM models are suitable to study these interactions. These are murine models that originate from spontaneously developed myeloma in elderly mice. They are propagated by in vivo transfer of the myeloma cells into young syngeneic mice. We report methods involving the maintenance of the 5T2MM model and the quantification of tumor burden (by determining serum paraprotein concentration and plasmacytosis), assessment of bone lesions, and quantification of angiogenesis. The combination of these different techniques in these models not only helps in unraveling basic biological processes but also in the testing of potentially new therapeutic targets.
Publisher: Wiley
Date: 12-1998
Publisher: No publisher found
Date: 1994
DOI: 10.1016/S0169-6009(08)80253-X
Abstract: Osteoporosis is characterised by reduced bone mass and disruption of cancellous bone architecture however, it is unknown whether these changes arise from a specific disease process or represent one extreme of physiological bone loss. We have quantitatively assessed cancellous structure in 35 patients with primary osteoporosis and 41 normal subjects. Cancellous microstructure was assessed by computerised strut analysis and by calculation of trabecular width, separation and number. Node to terminus ratio, node to node and node to loop strut length were significantly decreased in patients with osteoporosis when compared to normal subjects (P < 0.001), whereas terminus count and terminus to terminus strut length were significantly increased (P < 0.001). When two subgroups were matched for age these differences remained highly significant (P < 0.005). However, when two subgroups were matched for cancellous area, no significant differences were observed in any of the structural indices except terminus count (P < 0.05). Mean trabecular width and number were significantly lower and trabecular separation significantly higher in the patients with osteoporosis before and after age-matching but their differences disappeared after matching for cancellous area. Multiple regression analysis confirmed highly significant correlations between cancellous bone area and structural indices after adjustment for age, sex and disease status (P < 0.001). Our data demonstrate that for a given cancellous area, structural changes in primary osteoporosis are similar to those observed during age-related bone loss in normal subjects. These findings support the hypothesis that primary osteoporosis is the result of greater biological ageing rather than a specific disease process and are consistent with evidence from other sources that low bone mass is associated with increased mortality from diseases unrelated to osteoporosis.
Publisher: Bioscientifica
Date: 22-07-2014
DOI: 10.1530/ERC-14-0199
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.CELREP.2017.09.022
Abstract: The small GTPase RhoA is involved in a variety of fundamental processes in normal tissue. Spatiotemporal control of RhoA is thought to govern mechanosensing, growth, and motility of cells, while its deregulation is associated with disease development. Here, we describe the generation of a RhoA-fluorescence resonance energy transfer (FRET) biosensor mouse and its utility for monitoring real-time activity of RhoA in a variety of native tissues in vivo. We assess changes in RhoA activity during mechanosensing of osteocytes within the bone and during neutrophil migration. We also demonstrate spatiotemporal order of RhoA activity within crypt cells of the small intestine and during different stages of mammary gestation. Subsequently, we reveal co-option of RhoA activity in both invasive breast and pancreatic cancers, and we assess drug targeting in these disease settings, illustrating the potential for utilizing this mouse to study RhoA activity in vivo in real time.
Publisher: Elsevier BV
Date: 09-2018
Publisher: Wiley
Date: 06-2001
Publisher: Wiley
Date: 02-1999
DOI: 10.1046/J.1365-2141.1999.01193.X
Abstract: Interleukin-1beta(IL-1beta) and tumour necrosis factor-alpha (TNF-alpha) are potent bone resorbing cytokines that may contribute to the development of the osteolytic bone disease observed in patients with multiple myeloma (MM). Although these factors have been identified in cultures of bone marrow mononuclear cells isolated from patients, the identity of the cells responsible for producing IL-1beta and TNFalpha remains unclear. Using a sensitive dual-colour fluorescence in situ hybridization (FISH) technique and a two-colour immunofluorescence method we have investigated the expression of the mRNA and protein, for IL-1beta and TNFalpha, by in idual bone marrow plasma cells from patients with MM and monoclonal gammopathy of undetermined significance (MGUS). The mRNA for IL-1beta and TNFalpha was identified in all cells expressing the immunoglobulin light chain from all patients with MM and MGUS. However, the IL-1beta protein could not be detected in cytoplasmic light chain positive cells in any of the patients examined. In contrast, the TNFalpha protein was detected in clonal plasma cells from patients with both MM and MGUS. Interestingly, the IL-1beta and TNFalpha mRNA and proteins were readily detected within a small proportion of the non-plasma cells from patients with both MM and MGUS. These data suggest that myeloma cells in vivo are able to produce TNFalpha but not IL-1beta. In addition, a small proportion of accessory cells are likely to be able to contribute to the production of both ILbeta and TNFalpha.
Publisher: American Association for Cancer Research (AACR)
Date: 07-2009
DOI: 10.1158/0008-5472.CAN-08-4472
Abstract: The proteasome inhibitor bortezomib (Velcade) is currently approved as second-line treatment of multiple myeloma (MM). MM-related bone disease is one of the most debilitating complications of MM. Besides supportive care with biphosphonates, which have proven efficacy in reducing and delaying skeletal-related events, there is no specific treatment of lytic bone lesions. The present study investigated the effect of bortezomib alone or in combination with a hydroxamate-based histone deacetylase inhibitor, JNJ-26481585 on tumor burden, and MM bone disease in the 5T2MM model. Injection of 5T2MM cells into C57Bl/KaLwRij mice resulted in MM bone disease, characterized by an increase in the percentage osteoclasts, a decrease in osteoblasts, trabecular bone volume, trabecular number, and the development of bone lesions. Treatment of 5T2MM-bearing mice with bortezomib significantly reduced tumor burden, angiogenesis, and MM bone disease. More importantly, the combination of bortezomib with JNJ-26481585 resulted in a more pronounced reduction of osteoclasts and increase of osteoblasts, trabecular bone volume, and trabecular number compared with bortezomib as single agent. These data suggest that bortezomib has bone remodeling properties that can be improved in combination with low dose JNJ-26481585. The study indicates that this combination therapy could be a useful strategy for the treatment of MM patients, especially in those patients with skeletal complications. [Cancer Res 2009 (13):5307–11]
Publisher: Elsevier BV
Date: 08-2019
Publisher: Elsevier BV
Date: 1990
DOI: 10.1016/8756-3282(90)90076-B
Abstract: A computerised technique is described for the quantitative assessment of resorption cavities in iliac trabecular bone. Using an Ibas II image analyser, the original bone surface, eroded by bone resorbing cells, is reconstructed using a curve fitting technique that maintains a smooth continuity with the trabecular bone on either side of the cavity. Resorption depths are measured using an interactive elastic circle all identified cavities are measured regardless of whether or not resorption is complete, and the measurements made include mean and maximum cavity depth, cavity length, area, and adjacent trabecular widths. Results in 13 normal subjects are presented. The technique is reproducible, simple to operate, relatively rapid, and can be applied to less sophisticated image analysis systems.
Publisher: Wiley
Date: 02-02-2015
DOI: 10.1002/IJC.29439
Abstract: Dormant disseminated tumour cells can be detected in the bone marrow of breast cancer patients several years after resection of the primary tumour. The majority of these patients will remain asymptomatic, however, ∼ 15% will go on to develop overt bone metastases and this condition is currently incurable. The reason why these dormant cells are stimulated to proliferate and form bone tumours in some patients and not others remains to be elucidated. We have recently shown that in an in vivo model, increasing bone turnover by ovariectomy stimulated proliferation of disseminated tumour cells, resulting in formation of bone metastasis. We now show for the first time that osteoclast mediated mechanisms induce growth of tumours from dormant MDA-MB-231 cells disseminated in the bone. We also show that disruption of RANK-RANKL interactions following administration of OPG-Fc inhibits growth of these dormant tumour cells in vivo. Our data support early intervention with anti-resorptive therapy in a low-oestrogen environment to prevent development of bone metastases.
Publisher: eLife Sciences Publications, Ltd
Date: 19-06-2020
DOI: 10.7554/ELIFE.55549
Abstract: Functional characterisation of cell-type-specific regulatory networks is key to establish a causal link between genetic variation and phenotype. The osteoclast offers a unique model for interrogating the contribution of co-regulated genes to in vivo phenotype as its multinucleation and resorption activities determine quantifiable skeletal traits. Here we took advantage of a trans-regulated gene network (MMnet, macrophage multinucleation network) which we found to be significantly enriched for GWAS variants associated with bone-related phenotypes. We found that the network hub gene Bcat1 and seven other co-regulated MMnet genes out of 13, regulate bone function. Specifically, global (Pik3cb-/-, Atp8b2+/-, Igsf8-/-, Eml1-/-, Appl2-/-, Deptor-/-) and myeloid-specific Slc40a1 knockout mice displayed abnormal bone phenotypes. We report opposing effects of MMnet genes on bone mass in mice and osteoclast multinucleation/resorption in humans with strong correlation between the two. These results identify MMnet as a functionally conserved network that regulates osteoclast multinucleation and bone mass.
Publisher: Public Library of Science (PLoS)
Date: 10-04-2015
Publisher: EMBO
Date: 21-04-2020
Publisher: American Society of Hematology
Date: 15-04-2006
DOI: 10.1182/BLOOD-2005-09-3830
Abstract: ADAM-9, a member of the adisintegrin and metalloproteinase family, contains both metalloproteinase and disintegrin domains. Myeloma cell lines express ADAM-9 however, its function and role in the pathophysiology of multiple myeloma is unknown. The aim of this study was to establish whether primary myeloma cells express ADAM-9, whether ADAM-9 regulates IL-6 production in human osteoblasts (hOBs), whether ADAM-9 interacts with specific integrin heterodimers, and the identity of downstream signaling pathways. Primary myeloma cells demonstrated increased expression of ADAM-9 (P .01). ADAM-9 promoted a 5-fold increase in IL-6, but not IL-1β mRNA, and a dose- and time-dependent increase in IL-6 production by hOBs (P .01). IL-6 induction was inhibited by an antibody to the αvβ5 integrin (P .01) but not by antibodies to other integrin heterodimers. ADAM-9 was shown to bind directly to the αvβ5 integrin on hOBs. Antibodies to ADAM-9 and αvβ5 integrin inhibited myeloma cell–induced IL-6 production by hOBs (P .01). Furthermore, inhibitors of p38 MAPK and cPLA2, but not NF-κB and JAK2, signaling pathways inhibited ADAM-9–induced IL-6 production by hOBs (P .01). These data demonstrate that ADAM-9, expressed by myeloma cells, stimulates IL-6 production in hOBs by binding the αvβ5 integrin. This may have important consequences for the growth and survival of myeloma cells in bone.
Publisher: Public Library of Science (PLoS)
Date: 02-06-2015
Publisher: Elsevier BV
Date: 08-1991
Publisher: Springer Science and Business Media LLC
Date: 28-05-2021
Publisher: American Physiological Society
Date: 09-2010
Publisher: The Endocrine Society
Date: 09-2014
DOI: 10.1210/EN.2013-2156
Abstract: A new genetic disorder has been identified that results from mutation of THRA, encoding thyroid hormone receptor α1 (TRα1). Affected children have a high serum T3:T4 ratio and variable degrees of intellectual deficit and constipation but exhibit a consistently severe skeletal dysplasia. In an attempt to improve developmental delay and alleviate symptoms of hypothyroidism, patients are receiving varying doses and durations of T4 treatment, but responses have been inconsistent so far. Thra1PV/+ mice express a similar potent dominant-negative mutant TRα1 to affected in iduals, and thus represent an excellent disease model. We hypothesized that Thra1PV/+ mice could be used to predict the skeletal outcome of human THRA mutations and determine whether prolonged treatment with a supraphysiological dose of T4 ameliorates the skeletal abnormalities. Adult female Thra1PV/+ mice had short stature, grossly abnormal bone morphology but normal bone strength despite high bone mass. Although T4 treatment suppressed TSH secretion, it had no effect on skeletal maturation, linear growth, or bone mineralization, thus demonstrating profound tissue resistance to thyroid hormone. Despite this, prolonged T4 treatment abnormally increased bone stiffness and strength, suggesting the potential for detrimental consequences in the long term. Our studies establish that TRα1 has an essential role in the developing and adult skeleton and predict that patients with different THRA mutations will display variable responses to T4 treatment, which depend on the severity of the causative mutation.
Publisher: Elsevier BV
Date: 12-2008
DOI: 10.1016/J.BBRC.2008.09.157
Abstract: Geranylgeranyl transferase II (GGTase II) is an enzyme that plays a key role in the isoprenylation of proteins. 3-PEHPC, a novel GGTase II inhibitor, blocks bone resorption and induces myeloma cell apoptosis in vitro. Its effect on bone resorption and tumor growth in vivo is unknown. We investigated the effect of 3-PEHPC on tumor burden and bone disease in the 5T2MM model of multiple myeloma in vivo. 3-PEHPC significantly reduced osteoclast numbers and osteoclast surface. 3-PEHPC prevented the bone loss and the development of osteolytic bone lesions induced by 5T2MM myeloma cells. Treatment with 3-PEHPC also significantly reduced myeloma burden in bone. The magnitude of response was similar to that seen with the bisphosphonate, risedronate. These data show that targeting GGTase II with 3-PEHPC can prevent osteolytic bone disease and reduce tumor burden in vivo, and represents a novel approach to treating tumors that grow in bone.
Publisher: Elsevier BV
Date: 12-2010
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-08-2007
Publisher: Springer Science and Business Media LLC
Date: 08-05-2012
DOI: 10.1038/LEU.2012.126
Publisher: Springer Science and Business Media LLC
Date: 04-09-2017
DOI: 10.1038/NG.3949
Publisher: Wiley
Date: 15-05-2004
DOI: 10.1002/PROS.20016
Abstract: Osteoprotegerin (OPG) is a tumour and/or bone derived factor that may protect tumour cells from apoptosis. In this study, we have measured serum OPG levels in untreated prostate cancer patients with advanced prostate cancer compared to patients with organ confined disease and in treated patients receiving androgen ablation. Serum OPG levels were measured by ELISA in s les collected from 104 patients with either newly diagnosed (n = 59) or advanced prostate cancer treated by androgen ablation (n = 45) and compared with levels in serum from patients with benign prostatic hyperplasia (BPH) (n = 10) and young healthy men (n = 10). Untreated patients with locally advanced disease had significantly higher OPG levels than those with organ confined disease. Patients with advanced disease responding to androgen ablation (serum PSA 10 ng/ml). OPG levels in the latter were not significantly different from levels in patients with early signs of biochemical progression (PSA >1 but <10 ng/ml). OPG is a potential new marker, which is elevated in the serum of patients with advanced prostate cancer and may be an indicator of early disease progression.
Publisher: MDPI AG
Date: 07-05-2020
Abstract: Background: While critical insights have been gained from evaluating the genomic landscape of metastatic prostate cancer, utilizing this information to inform personalized treatment is in its infancy. We performed a retrospective pilot study to assess the current impact of precision medicine for locally advanced and metastatic prostate adenocarcinoma and evaluate how genomic data could be harnessed to in idualize treatment. Methods: Deep whole genome-sequencing was performed on 16 tumour-blood pairs from 13 prostate cancer patients whole genome optical mapping was performed in a subset of 9 patients to further identify large structural variants. Tumour s les were derived from prostate, lymph nodes, bone and brain. Results: Most s les had acquired genomic alterations in multiple therapeutically relevant pathways, including DNA damage response (11/13 cases), PI3K (7/13), MAPK (10/13) and Wnt (9/13). Five patients had somatic copy number losses in genes that may indicate sensitivity to immunotherapy (LRP1B, CDK12, MLH1) and one patient had germline and somatic BRCA2 alterations. Conclusions: Most cases, whether primary or metastatic, harboured therapeutically relevant alterations, including those associated with PARP inhibitor sensitivity, immunotherapy sensitivity and resistance to androgen pathway targeting agents. The observed intra-patient heterogeneity and presence of genomic alterations in multiple growth pathways in in idual cases suggests that a precision medicine model in prostate cancer needs to simultaneously incorporate multiple pathway-targeting agents. Our whole genome approach allowed for structural variant assessment in addition to the ability to rapidly reassess an in idual’s molecular landscape as knowledge of relevant biomarkers evolve. This retrospective oncological assessment highlights the genomic complexity of prostate cancer and the potential impact of assessing genomic data for an in idual at any stage of the disease.
Publisher: Wiley
Date: 09-1997
DOI: 10.1046/J.1365-2141.1997.2713086.X
Abstract: Bisphosphonates are in widespread use to prevent bone resorption in a number of metabolic and tumour-induced bone diseases including multiple myeloma. Recent reports suggest that bisphosphonate treatment may be associated with an increase in patient survival, raising the possibility that these compounds may have a direct effect on the tumour cells. We have investigated whether the bisphosphonates clodronate, pamidronate and YM175 can directly affect the human myeloma cell lines U266-B1, JJN-3 and HS-Sultan in vitro. The effect of bisphosphonate treatment on cell number and cell cycle progression was examined using flow cytometry. The ability of bisphosphonates to induce apoptosis in human myeloma cell lines was determined on the basis of changes in nuclear morphology and of DNA fragmentation. Pamidronate and the more potent bisphosphonate. YM175, significantly decreased cell number (P < 0.001) in JJN-3 and HS-Sultan cells. YM175 also caused cells to arrest in the S-phase of the cell cycle in the JJN-3 cell line. Both pamidronate and YM175 also caused an increase in the proportion of cells with altered nuclear morphology (P < 0.05) and fragmented DNA, characteristic of apoptosis, in both JJN-3 and HS-Sultan cells. In contrast, clodronate had little effect on cell number and did not cause apoptosis at the concentrations examined. These data raise the possibility that some bisphosphonates could have direct anti-tumour effects on human myeloma cells in vivo.
Publisher: Elsevier BV
Date: 2011
Publisher: No publisher found
Date: 2000
DOI: 10.1046/J.1365-2141.2000.01845.X
Abstract: Interleukin-6 (IL-6) is an important growth and survival factor for myeloma cells. However, the identity of the cells producing IL-6 in vivo remains unclear. Myeloma cells are found closely associated with sites of active bone turnover, and cells of the osteogenic lineage, including bone marrow osteoprogenitors, osteoblasts and bone lining cells, may therefore be ideally placed to synthesize IL-6. We have examined the possibility that human osteogenic cells may produce IL-6 in response to stimulation by myeloma cells. Primary human osteoblasts (hOBs) were isolated from normal donors, co-cultured with the human myeloma cell lines, JJN-3, RPMI-8226 and NCI-H929, and the amount of IL-6 released was determined by enzyme-linked immunosorbent assay (ELISA). All myeloma cells stimulated a significant increase in the production of IL-6 when cultured with hOBs (P < 0.05). Prior fixation of hOBs completely abrogated release of IL-6 in the co-cultures. In contrast, fixed myeloma cells retained the ability to induce IL-6 production, suggesting that hOBs were the principal source of IL-6. Physical separation of myeloma cells from hOBs using transwell inserts caused a partial inhibition of IL-6 release (P < 0.05), whereas the addition of media conditioned by myeloma cells to cultures of hOBs stimulated a significant increase in IL-6 production (P < 0.05). hOBs secreted greater amounts of IL-6 than human bone marrow stromal cells (hBMSCs) (2.2- to 3.5-fold, P < 0.05), but incubating hBMSCs with dexamethasone to stimulate osteoblastic differentiation resulted in an increase in their ability to produce IL-6 (1.7- to 4. 8-fold, P < 0.05) and to respond to myeloma cells (P < 0.05). These data clearly indicate that cells of the osteoblast lineage release significant amounts of IL-6 in response to stimulation by myeloma cells and may contribute to the IL-6 that promotes the proliferation and survival of myeloma cells in vivo.
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 05-11-2021
DOI: 10.3324/HAEMATOL.2020.253526
Abstract: Multiple myeloma (MM) disease progression is dependent on the ability of MM plasma cells (PC) to egress from the bone marrow (BM), enter the circulation and disseminate to distal BM sites. Expression of the chemokine CXCL12 by BM stromal cells is crucial for MM PC retention within the BM. However, the mechanisms which overcome CXCL12-mediated retention to enable dissemination are poorly understood. We have previously identified that treatment with the CCR1 ligand CCL3 inhibits the response to CXCL12 in MM cell lines, suggesting that CCL3/CCR1 signaling may enable egress of MM PC from the BM. Here, we demonstrated that CCR1 expression was an independent prognostic indicator in newly diagnosed MM patients. Furthermore, we showed that CCR1 is a crucial driver of dissemination in vivo, with CCR1 expression in the murine MM cell line 5TGM1 being associated with an increased incidence of bone and splenic disseminated tumors in C57BL/KaLwRij mice. Furthermore, we demonstrated that CCR1 knockout in the human myeloma cell line OPM2 resulted in a % reduction in circulating MM PC numbers and BM and splenic tumor dissemination following intratibial injection in NSG mice. Therapeutic targeting of CCR1 with the inhibitor CCX9588 significantly reduced OPM2 or RPMI-8226 dissemination in intratibial xenograft models. Collectively, our findings suggest a novel role for CCR1 as a critical driver of BM egress of MM PC during tumor dissemination. Furthermore, these data suggest that CCR1 may represent a potential therapeutic target for the prevention of MM tumor dissemination.
Publisher: Cold Spring Harbor Laboratory
Date: 23-09-2019
Publisher: Cold Spring Harbor Laboratory
Date: 22-04-2020
DOI: 10.1101/2020.04.20.051409
Abstract: Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this program is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders (P=2.4×10 -22 ) and are associated with the polygenic diseases osteoporosis (P=1.8×10 -13 ) and osteoarthritis (P=1.6×10 -7 ). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease.
Publisher: Elsevier BV
Date: 10-1993
DOI: 10.1016/S0169-6009(08)80088-8
Abstract: The current concept of bone remodelling is based on the belief that bone resorption and formation are coupled both in time and space this implies that the surface extent of bone eroded in a bone remodelling unit would approximate to the surface extent of the osteoid seam formed subsequently. The greater total surface extent of osteoid as opposed to erosion is generally attributed to the longer life-span of bone formation, but no comparison of the length of eroded surface and osteoid seam within in idual bone remodelling units has been reported. In this study we have compared the length of in idual osteoid seams, resorption cavities and bone structural units in iliac crest trabecular bone obtained from normal subjects and from patients with renal osteodystrophy. Values for osteoid seam and bone packet length were significantly greater than resorption cavity length in both the normal and patient groups (P < 0.001), the ratio of osteoid seam and eroded length being similar in the two groups (1:0.44 and 1:0.40, respectively). These results indicate that the discrepancy between total osteoid and eroded surface extent cannot be wholly explained on the basis of a longer formation life-span. Possible additional explanations include underestimation of eroded surface by light microscopic techniques, initiation of bone formation within a cavity before the completion of resorption, the presence of arrested resorption cavities, non-random distribution of resorption cavities on the trabecular surface and bone formation on quiescent bone surfaces.
Publisher: Springer Science and Business Media LLC
Date: 09-1991
DOI: 10.1007/BF03187471
Publisher: Springer Science and Business Media LLC
Date: 20-01-2021
DOI: 10.1038/S41467-020-20761-5
Abstract: Osteoarthritis causes debilitating pain and disability, resulting in a considerable socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in randomly selected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1 , and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we phenotype previously generated mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by CRISPR/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. We hope this expanding resource of mutant mice will accelerate functional gene discovery in osteoarthritis and offer drug discovery opportunities for this common, incapacitating chronic disease.
Publisher: Public Library of Science (PLoS)
Date: 02-08-2012
Publisher: BMJ
Date: 03-1994
DOI: 10.1136/ARD.53.3.163
Abstract: To examine whether changes in cancellous bone turnover and resorption cavity depth contribute to bone loss in patients with non-steroid treated rheumatoid arthritis. Iliac crest biopsies were obtained from 37 patients with non-steroid treated rheumatoid arthritis, 13 male and 24 female, aged 37-71 years. Bone turnover and resorption cavity characteristics were quantitatively assessed using semiautomated computerised techniques. When compared with age- and sex-matched control values, there was a significant reduction in bone formation rate at tissue level and activation frequency (P < 0.001) in the patient group. The eroded perimeter, mean and maximum eroded depth and cavity area were also significantly reduced (P < 0.01, < 0.005, < 0.01 and < 0.005 respectively). These results demonstrate low bone turnover in non-steroid treated rheumatoid arthritis and indicate that the reduced bone mass in these patients is due mainly to a negative remodelling balance.
Publisher: Elsevier BV
Date: 12-2003
DOI: 10.1016/S1074-7613(03)00326-1
Abstract: Autoimmune associated bone disease and intestinal inflammation are closely linked with deregulation and hyperactivation of autoreactive CD4 T cells. How these T cells are activated and mediate disease is not clear. Here we show that in the Interleukin 2-deficient mouse model of autoimmunity spontaneous osteopenia and colitis are caused by increased production of the ligand for receptor activator of NFkappaB (RANKL). RANKL acting via its receptor, receptor activator of NFkappaB (RANK), increases bone turnover and promotes intestinal dendritic cell (DC) survival in vivo. Modulation of RANKL-RANK interactions with exogenous recombinant osteoprotegerin (Fc-OPG) reverses skeletal abnormalities and reduces colitis by decreasing colonic DC numbers. This study identifies a common causal link between bone disease and intestinal inflammation and establishes the importance of DC in mediating colonic inflammation in vivo.
Publisher: Elsevier BV
Date: 2018
Publisher: Springer Science and Business Media LLC
Date: 06-11-2017
DOI: 10.1007/S00223-017-0338-4
Abstract: Wnt antagonist Dkk1 is a negative regulator of bone formation and Dkk1
Publisher: Public Library of Science (PLoS)
Date: 16-05-2012
Publisher: Informa UK Limited
Date: 2000
DOI: 10.1080/028418600750063587
Abstract: Bisphosphonates are a class of anti-resorptive drugs, which are effective in the treatment of osteoclast-mediated bone disease, including the osteolytic bone disease. which is a major clinical feature of patients with multiple myeloma. Recently, increases in survival following treatment with pamidronate have been observed in some patients with multiple myeloma, raising the possibility that bisphosphonates may also have an anti-tumour effect. We have demonstrated that bisphosphonates can have an anti-tumour effect in human myeloma cell in vitro, and that these anti-tumour effects induced by potent nitrogen-containing bisphosphonates are a result of inhibition of enzymes of the mevalonate pathway. However, we and others have been unable to demonstrate an anti-tumour effect of the potent bisphosphonate ibandronate in vivo, using murine models of multiple myeloma. It is therefore likely that only by studying patients receiving bisphosphonates will we be able to determine whether these compounds have a clinically important anti-tumour effect.
Publisher: Wiley
Date: 21-02-2007
DOI: 10.1002/IJC.22478
Abstract: Apomine, a novel 1,1 bisphosphonate ester, increases the rate of degradation of HMG-CoA reductase, inhibiting the mevalonate pathway and thereby blocking cholesterol biosynthesis. We have investigated whether Apomine can induce myeloma cell apoptosis in vitro and modulate myeloma disease in vivo. Apomine induced a dose-dependent increase in apoptosis in NCI H929, RPMI 8226 and JJN-3 human myeloma cells. Apomine, unlike the bisphosphonate, alendronate, had no measurable effect on osteoclastic bone resorption in vitro. To investigate the effect of Apomine in vivo, 5T2MM murine myeloma cells were injected into C57BL/KaLwRij mice. After 8 weeks all animals had a serum paraprotein and were treated with Apomine (200 mg/kg), or vehicle, for 4 weeks. Animals injected with 5T2MM cells and treated with vehicle developed osteolytic bone lesions, reduced cancellous bone area, decreased bone mineral density (BMD) and increased osteoclast number. Apomine caused a decrease in serum paraprotein and a decrease in tumor burden. Apomine inhibited the development of osteolytic lesions and prevented the tumor-induced decreases in BMD. Apomine had no effect on osteoclast number in contrast to what had been seen previously with the bisphosphonate, zoledronic acid, suggesting that these are direct effects of Apomine on myeloma cells. This demonstrates that Apomine is able to promote myeloma cell apoptosis in vitro and inhibit the development of multiple myeloma and lytic bone disease in vivo. The use of bisphosphonate esters such as Apomine represents a novel therapeutic approach in the treatment of myeloma and, indirectly, the associated bone disease.
Publisher: Public Library of Science (PLoS)
Date: 13-12-2016
Publisher: American Association for Cancer Research (AACR)
Date: 29-05-2014
DOI: 10.1158/1078-0432.CCR-13-1246
Abstract: Purpose: Clinical trials in early breast cancer have suggested that benefits of adjuvant bone-targeted treatments are restricted to women with established menopause. We developed models that mimic pre- and postmenopausal status to investigate effects of altered bone turnover on growth of disseminated breast tumor cells. Here, we report a differential antitumor effect of zoledronic acid (ZOL) in these two settings. Experimental design: Twleve-week-old female Balb/c-nude mice with disseminated MDA-MB-231 breast tumor cells in bone underwent sham operation or ovariectomy (OVX), mimicking the pre- and postmenopausal bone microenvironment, respectively. To determine the effects of bone-targeted therapy, sham/OVX animals received saline or 100 μg/kg ZOL weekly. Tumor growth was assessed by in vivo imaging and effects on bone by real-time PCR, micro-CT, histomorphometry, and measurements of bone markers. Disseminated tumor cells were detected by two-photon microscopy. Results: OVX increased bone resorption and induced growth of disseminated tumor cells in bone. Tumors were detected in 83% of animals following OVX (postmenopausal model) compared with 17% following sham operation (premenopausal model). OVX had no effect on tumors outside of bone. OVX-induced tumor growth was completely prevented by ZOL, despite the presence of disseminated tumor cells. ZOL did not affect tumor growth in bone in the sham-operated animals. ZOL increased bone volume in both groups. Conclusions: This is the first demonstration that tumor growth is driven by osteoclast-mediated mechanisms in models that mimic post- but not premenopausal bone, providing a biologic rationale for the differential antitumor effects of ZOL reported in these settings. Clin Cancer Res 20(11) 2922–32. ©2014 AACR.
Publisher: Elsevier BV
Date: 03-2010
Publisher: American Society of Hematology
Date: 15-12-2001
Publisher: Elsevier BV
Date: 03-2021
Publisher: Elsevier BV
Date: 10-2007
Publisher: American Society of Hematology
Date: 15-08-2007
DOI: 10.1182/BLOOD-2007-03-067710
Abstract: Bone disease is one of the most debilitating manifestations of multiple myeloma. A complex interdependence exists between myeloma bone disease and tumor growth, creating a vicious circle of extensive bone destruction and myeloma progression. Proteasome inhibitors have recently been shown to promote bone formation in vitro and in vivo. Preclinical studies have demonstrated that proteasome inhibitors, including bortezomib, which is the first-in-class such agent, stimulate osteoblast differentiation while inhibiting osteoclast formation and bone resorption. Clinical studies are confirming these observations. Bortezomib counteracts the abnormal balance of osteoclast regulators (receptor activator of nuclear factor-κB ligand and osteoprotegerin), leading to osteoclast inhibition and decreased bone destruction, as measured by a reduction in markers of bone resorption. In addition, bortezomib stimulates osteoblast function, possibly through the reduction of dickkopf-1, leading to increased bone formation, as indicated by the elevation in bone-specific alkaline phosphatase and osteocalcin. The effect of bortezomib on bone disease is thought to be direct and not only a consequence of the agent's antimyeloma properties, making it an attractive agent for further investigation, as it may combine potent antimyeloma activity with beneficial effects on bone. However, the clinical implication of these effects requires prospective studies with specific clinical end points.
Publisher: Springer Science and Business Media LLC
Date: 04-09-2008
DOI: 10.1038/LEU.2008.235
Abstract: This phase 2 study aimed to determine the efficacy and safety of the combination of bortezomib, melphalan, dexamethasone and intermittent thalidomide (VMDT) and its effect on bone remodeling and angiogenesis in relapsed/refractory myeloma. Bortezomib (1.0 mg/m(2)) was given on days 1, 4, 8, 11, oral melphalan (0.15 mg/kg) on days 1-4, whereas thalidomide (100 mg per day) and dexamethasone (12 mg/m(2)) were administered on days 1-4 and 17-20 of a 28-day cycle, for four cycles. Patients without disease progression continued for up to eight cycles. VMDT effect on bone remodeling was evaluated by measuring osteoclast regulators (soluble receptor activator of nuclear factor-kappa B ligand/osteoprotegerin ratio, osteopontin, macrophage inflammatory protein-1alpha), dickkopf-1 protein, bone resorption and formation markers, whereas its effect on angiogenesis was assessed by measuring serum vascular endothelial growth factor, angiogenin, angiopoietin-2 and basic fibroblast growth factor, after four cycles and at the study end. A total of 62 patients were enrolled. The overall response rate was 66%: CR 13%, vgPR 27% and PR 26%. Median time to response was 35 days and median time to progression was 9.3 months. Common adverse events included cytopenias, peripheral neuropathy and infections. No patient experienced deep-vein thrombosis. VMDT reduced angiogenic cytokines, osteoclast regulators, dickkopf-1 and bone resorption. We conclude that VMDT with intermittent thalidomide is an active and well-tolerated regimen for relapsed/refractory myeloma, affecting abnormal bone remodeling and angiogenesis.
Publisher: Elsevier BV
Date: 2001
DOI: 10.1016/S0301-472X(00)00625-1
Abstract: Multiple myeloma, a plasma cell malignancy, is predominantly localized in the bone marrow. These tumoral cells display a heterogeneous expression of CD45. It is, however, unclear which subpopulation is responsible for the homing and outgrowth of the myeloma cells. In this work, we investigated the in vivo homing, proliferation, and differentiation of both CD45+ and CD45- cells in two murine myeloma models.5T2MM and 5T33MM in vivo lines of murine multiple myeloma were used. CD45 and IGF-I receptor expression was analyzed by FACS. Proliferative capacity was assessed by in vivo bromodeoxyuridine incorporation. 5TMM cells were separated into CD45+ and CD45- fractions by MACS. Initial homing was investigated in vivo by tracing of radioactively labeled cells. Myeloma cells were detected by FACS and histology. Osteolytic lesions were analyzed by radiography. Both CD45+ and CD45- 5TMM cells were able to home to the bone marrow, although the migration of the latter subset was lower, which was related to a low IGF-I receptor expression. Recipients of both fractions developed myeloma as evidenced by the presence of serum paraprotein, osteolytic lesions, and bone marrow infiltration by myeloma cells. The tumor load in the recipients of CD45- cells was higher than the CD45+ cells, which could be explained by a lower proliferation rate of the latter population. While the separated cells before injection had a homogenous expression of CD45, cells isolated from the bone marrow of these terminally diseased mice had a heterogeneous expression pattern, indicating an in vivo differentiation pattern of CD45- to CD45+ cells and vice versa. We conclude that both CD45+ and CD45- 5TMM subpopulations contain clonogenic myeloma cells with bone marrow homing and proliferative capacity.
Publisher: Springer Science and Business Media LLC
Date: 26-07-2007
Abstract: We describe a new model of myeloma bone disease in which beta2m NOD/SCID mice injected with KMS-12-BM cells develop medullary disease after tail vein administration. Micro-computed tomography analysis demonstrated significant bone loss in the tibiae and vertebrae of diseased animals compared to controls, with loss of cortical bone (P<0.01), as well as trabecular bone volume, thickness and number (P<0.05 for all). Bone marrow of diseased animals demonstrated an increase in osteoclasts (P<0.01) and reduction in osteoblasts (P<0.01) compared to control animals. Both bone loss and osteoclast increase correlated with the degree of disease involvement. Mesenchymal stem cells (MSCs) were lentivirally transduced to express human osteoprotegerin (hOPG). Systemic administration of OPG expressing MSC reduced osteoclast activation (P<0.01) and trabecular bone loss in the vertebrae (P<0.05) and tibiae of diseased animals, to levels comparable to non-diseased controls. Because of its predominantly medullary involvement and quantifiable parameters of bone disease, the KMS-12-BM xenogeneic model provides unique opportunities to test therapies targeted at the bone marrow microenvironment.
Publisher: Wiley
Date: 06-06-2017
DOI: 10.1002/JCP.25976
Abstract: The bone marrow niche is a dynamic and complex microenvironment that can both regulate, and be regulated by the bone matrix. Within the bone marrow (BM), mesenchymal stromal cell (MSC) precursors reside in a multi‐potent state and retain the capacity to differentiate down osteoblastic, adipogenic, or chondrogenic lineages in response to numerous biochemical cues. These signals can be altered in various pathological states including, but not limited to, osteoporotic‐induced fracture, systemic adiposity, and the presence of bone‐homing cancers. Herein we provide evidence that signals from the bone matrix (osteocytes) determine marrow adiposity by regulating adipogenesis in the bone marrow. Specifically, we found that physiologically relevant levels of Sclerostin (SOST), which is a Wnt‐inhibitory molecule secreted from bone matrix‐embedded osteocytes, can induce adipogenesis in 3T3‐L1 cells, mouse ear‐ and BM‐derived MSCs, and human BM‐derived MSCs. We demonstrate that the mechanism of SOST induction of adipogenesis is through inhibition of Wnt signaling in pre‐adipocytes. We also demonstrate that a decrease of sclerostin in vivo, via both genetic and pharmaceutical methods, significantly decreases bone marrow adipose tissue (BMAT) formation. Overall, this work demonstrates a direct role for SOST in regulating fate determination of BM‐adipocyte progenitors. This provides a novel mechanism for which BMAT is governed by the local bone microenvironment, which may prove relevant in the pathogenesis of certain diseases involving marrow adipose. Importantly, with anti‐sclerostin therapy at the forefront of osteoporosis treatment and a greater recognition of the role of BMAT in disease, these data are likely to have important clinical implications.
Publisher: Cold Spring Harbor Laboratory
Date: 25-02-2019
DOI: 10.1101/560565
Abstract: To identify targets for novel anabolic medicines for osteoporosis, we recruited a large cohort with unexplained high bone mass (HBM). Exome sequencing identified a rare (minor allele frequency 0.0014) missense mutation in SMAD9 (c.65T C, p.Leu22Pro) segregating with HBM in an autosomal dominant family. The same mutation was identified in another two unrelated in iduals with HBM. In-silico protein modelling predicts the mutation severely disrupts the MH1 DNA-binding domain of SMAD9. Affected in iduals have bone mineral density [BMD] Z-Scores +3 to +5, with increased volumetric cortical and trabecular BMD, increased cortical thickness, and low/normal bone turnover. Fractures and nerve compressions are not seen. Both genome-wide, and gene-based association testing of heel estimated-BMD in ,924 UK-Biobank British subjects showed strong associations with SMAD9 (P GWAS =6×10 −16 P GENE =8×10 −17 ). Smad9 is highly expressed in murine osteocytes and zebrafish bone tissue. Our findings support SMAD9 as a novel HBM gene, and a potential novel osteoanabolic target.
Publisher: Bentham Science Publishers Ltd.
Date: 09-2010
DOI: 10.2174/138161210793563608
Abstract: Multiple myeloma is an incurable B cell neoplasm caused by the monoclonal expansion of malignant plasma cells in the bone marrow, often resulting in devastating bone disease. For over 2 decades bisphosphonates have been successfully used to treat the tumour-induced bone disease associated with multiple myeloma. This review will focus on preclinical studies and investigations in patients with multiple myeloma that have led to our current understanding of the mechanisms of action of bisphosphonates in myeloma bone disease. Major advances in the use of bisphosphonates, including findings that they may have additional benefits such as anti-tumour effects and promoting patient survival will be discussed.
Publisher: Elsevier BV
Date: 08-2003
DOI: 10.1016/S0960-9776(03)80161-3
Abstract: Bone is a favorable microenvironment for tumor cell colonization because of abundant growth factors released during active bone resorption. Bisphosphonates can dramatically affect the ability of tumor cells to grow in bone by inhibiting osteoclast-mediated bone resorption and by depriving tumors of growth-promoting signals. Moreover, bisphosphonates have direct anti-tumor effects in vitro via induction of apoptosis. Zoledronic acid is a nitrogen-containing bisphosphonate that has demonstrated potent anti-tumor activity in vitro and in vivo. In vitro studies have provided important clues as to the molecular mechanisms by which zoledronic acid induces apoptosis of human breast cancer cell lines. Studies in multiple myeloma and breast cancer models have shed further light on the possible mechanisms underlying the in vivo anti-tumor effects of zoledronic acid. These studies have led to the development of novel strategies to target specific molecular pathways involved in osteoclast maturation and activity, tumor cell metastasis, and tumor growth and survival. The clinical application of these strategies may ultimately prevent bone metastasis.
Publisher: Wiley
Date: 06-1998
DOI: 10.1046/J.1365-2141.1998.00754.X
Abstract: Interleukin-6 (IL-6) is the major growth factor for human myeloma cells, exerting its effect through the IL-6 receptor (IL-6R). A soluble form of IL-6R (sIL-6R) has been identified, which increases the sensitivity of myeloma cells to IL-6. In patients with multiple myeloma (MM), serum concentrations of sIL-6R are elevated and associated with poor prognosis. The present study was undertaken to determine whether proteolytic cleavage of IL-6R could contribute to sIL-6R release from human myeloma cells, and also to identify the class of proteinase responsible for this event. Human myeloma cell lines were shown to express IL-6R upon their surface and also to release sIL-6R into culture supernatants. In addition, phorbol 12-myristate 13-acetate (PMA) stimulated a loss of IL-6R from the cell surface, with a corresponding increase in the concentration of sIL-6R in the supernatant. Inhibitors of serine and cysteine proteinases, and tissue inhibitor of metalloproteinase (TIMP) -1 and TIMP-2, were shown to have no effect on the magnitude of sIL-6R release. In contrast, TIMP-3 and a hydroxamate-based metalloproteinase inhibitor (BB-94), inhibited both constitutive and PMA-induced release of sIL-6R. Myeloma cells freshly isolated from the bone marrow of a patient with MM were also shown to express IL-6R upon their surface, and to shed this receptor in response to PMA. These data demonstrate that increased proteolytic cleavage of IL-6R, mediated by a non-matrix-type metalloproteinase, is likely to contribute to the elevated concentrations of sIL-6R found in the serum of patients with MM. Inhibition of sIL-6R release by hydroxamate-based metalloproteinase inhibitors may represent a novel therapeutic approach to the treatment of MM.
Publisher: Wiley
Date: 10-1995
Abstract: Bone resorption and formation are coupled both in time and space and may occur simultaneously in the same remodeling unit. A number of studies have shown that the formative phase of the remodeling sequence may undergo temporary interruptions prior to completion and it is possible that bone resorption may be subject to similar interruptions. We have investigated this hypothesis by studying the distribution of eroded depth in resorption cavities in human cancellous bone. Eroded depth was assessed in iliac crest cancellous bone from 41 normal healthy subjects using a cubic spline curve fitting technique. The distribution of mean eroded depths was skewed to the right. Comparison of the observed distribution with an expected distribution, which was calculated from previously published data and assumes resorption begins rapidly and slows as it approaches completion, showed a significantly greater proportion of shallower cavities than expected (p<0001). Similarly, comparison of observed and uniform distributions, which assumes a constant rate of resorption throughout the erosion period, also showed a significantly greater proportion of smaller cavities (p<0.01). In subjects aged less than 39 years, there were fewer small cavities than in those aged 40-59 years. In addition, there was some evidence that females of 40-59 years had a proportionately greater number of smaller cavities than males however, there were no differences in other age groups. Our results demonstrate a significantly greater proportion of smaller resorption cavities than would be expected from current models of bone remodeling and are consistent with the hypothesis that resorption undergoes temporary interruptions and/or permanent arrest during the process of bone remodeling.
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2007
DOI: 10.1158/0008-5472.CAN-06-4361
Abstract: The bone microenvironment plays a critical role in supporting the growth and survival of multiple myeloma as well as in the development of osteolytic bone disease. Signaling through p38α mitogen-activated protein kinase (MAPK) mediates synthesis of multiple myeloma cell growth factors, and its inhibition reduces proliferation in vitro. However, it is unclear whether targeting p38α MAPK prevents multiple myeloma growth and the development of bone disease in vivo. In this study, we determined whether SCIO-469, a selective p38α MAPK inhibitor, inhibits multiple myeloma growth and prevents bone disease in the 5T2MM and 5T33MM models. SCIO-469 decreased constitutive p38α MAPK phosphorylation of both 5T2MM and 5T33MM cells in vitro. This was associated with decreased DNA synthesis and an induction of apoptosis when the cells were cultured with bone marrow stromal cells. Treatment of C57Bl/KaLwRij mice bearing 5T33MM cells with SCIO-469 inhibited p38α MAPK phosphorylation and was associated with a significant decrease in serum paraprotein, an almost complete reduction in tumor cells in the bone marrow, a decrease in angiogenesis, and a significant increase in disease-free survival. Injection of 5T2MM murine myeloma cells into C57Bl/KaLwRij mice resulted in myeloma bone disease characterized by increased osteoclast occupation of the bone surface, reduced cancellous bone, and the development of osteolytic bone lesions. Treatment of 5T2MM-injected mice with SCIO-469 reduced this development of bone disease. Together, these data show that targeting p38α MAPK with SCIO-469 decreases myeloma burden in vivo, in addition to preventing the development of myeloma bone disease. [Cancer Res 2007 (10):4572–7]
Publisher: Wiley
Date: 02-11-2015
DOI: 10.1111/BJH.13790
Abstract: Myeloma bone disease results from an uncoupling of osteoclastic resorption and osteoblastic bone formation, but early changes in osteogenic function remain poorly defined. We used the KMS12BM xenograft model to investigate cellular and molecular events at early and late stages of disease. Lytic lesions and changes in osteoblast and osteoclast numbers occur late (8 weeks), however, micro-computed tomography of femora revealed significant reduction in bone volume at earlier disease stages (3 weeks) when tumour burden is low. Calcein labelling demonstrated reduced mineralization and bone formation at 3 weeks, suggesting functional impairment despite preserved osteoblast numbers. Osteo-progenitors from compact bone increased early (1 week), but fell at 3 weeks and were profoundly suppressed by 8 weeks. Exposure of osteoblast progenitors to multiple myeloma (MM) cells in vitro induced cell cycling, suggesting a mechanistic basis for early expansion of osteo-progenitors. We observed temporal changes in chemokine, osteogenic and osteoclastogenic genes in the stromal compartment. Notably, an early rise in CCL3 may underlie functional changes in mature osteoblasts at 3 weeks. Our data indicate that MM has distinct effects on mature osteoblasts and immature osteo-progenitors. Our findings argue for early clinical intervention to prevent bone changes that ultimately lead to the development of osteolytic disease.
Publisher: Springer Science and Business Media LLC
Date: 02-06-2020
Publisher: Springer Science and Business Media LLC
Date: 03-1990
DOI: 10.1007/BF02555037
Publisher: Bentham Science Publishers Ltd.
Date: 04-2010
DOI: 10.2174/138161210791034021
Abstract: Cancers which damage the human skeleton include multiple myeloma, where the primary tumour colonises bone directly, or breast and prostate cancer, where malignant cells travel from the primary tumour to form clonal outgrowths within the bone. Owing to the interaction of tumour cells with those normally found in the bone microenvironment, such as osteoclasts and osteoblasts, these cancers affect the closely linked processes of bone formation and resorption. As a result, these twin processes contribute to the clinical manifestations of cancer metastasis, including bone pain and pathological fractures. A critical component of physiologically normal bone remodelling, the RANK/RANKL/OPG pathway, has been implicated in the formation of osteolytic, and possibly osteoblastic, lesions, which characterise the bone disease associated with these malignancies. In these cancers that affect the skeleton in this way the abnormally regulated RANK/RANKL system appears to be the final effector pathway. As a result, there has been much research focused upon targeting these molecules using OPG constructs, peptidomimetics, soluble receptor constructs and antibodies to RANKL, in pre-clinical studies. The success of these studies has paved the way for a clinical programme, the success of which is likely to lead to a new therapeutic approach to treating cancers that develop in the skeleton.
Publisher: Proceedings of the National Academy of Sciences
Date: 05-04-2010
Abstract: Hypothyroidism and thyrotoxicosis are each associated with an increased risk of fracture. Although thyroxine (T4) is the predominant circulating thyroid hormone, target cell responses are determined by local intracellular availability of the active hormone 3,5,3′-L-triiodothyronine (T3), which is generated from T4 by the type 2 deiodinase enzyme (D2). To investigate the role of locally produced T3 in bone, we characterized mice deficient in D2 (D2KO) in which the serum T3 level is normal. Bones from adult D2KO mice have reduced toughness and are brittle, displaying an increased susceptibility to fracture. This phenotype is characterized by a 50% reduction in bone formation and a generalized increase in skeletal mineralization resulting from a local deficiency of T3 in osteoblasts. These data reveal an essential role for D2 in osteoblasts in the optimization of bone strength and mineralization.
Publisher: Elsevier BV
Date: 05-1993
Publisher: Wiley
Date: 05-1998
DOI: 10.1046/J.1365-2141.1998.00687.X
Abstract: Interleukin-6 (IL-6) is an important growth factor for human myeloma cells in vitro and in vivo. However, the identity of the cells producing IL-6 in vivo in patients with multiple myeloma (MM) remains the subject of debate. We have developed a sensitive dual-colour fluorescence in situ hybridization (FISH) technique to investigate the expression of IL-6 mRNA by in idual bone marrow plasma cells from patients with multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS) and healthy subjects. IL-6 mRNA could be identified in all immunoglobulin light chain (IgLC) expressing cells from all patients with MM and MGUS. The IL-6 protein could also be detected by direct immunofluorescence in all plasma cells (cytoplasmic light chain positive) from all patients with MM and MGUS. Furthermore, it was also possible to demonstrate cytoplasmic IL-6 staining of plasma cells from patients with MM by flow cytometric analysis. In contrast, neither the IL-6 mRNA or protein could be detected in normal plasma cells from healthy bone marrow donors. These data demonstrate that plasma cells from patients with MM and MGUS express the IL-6 mRNA and synthesize the IL-6 protein and support the hypothesis that autocrine synthesis of IL-6 is of importance in patients with MM.
Publisher: Wiley
Date: 14-11-2019
DOI: 10.1002/JBMR.3875
Publisher: Elsevier BV
Date: 10-2019
Publisher: Wiley
Date: 12-2014
DOI: 10.1002/JBMR.2300
Abstract: It has been suggested that metastasis-initiating cells gain a foothold in bone by homing to a metastastatic microenvironment (or "niche"). Whereas the precise nature of this niche remains to be established, it is likely to contain bone cell populations including osteoblasts and osteoclasts. In the mouse tibia, the distribution of osteoblasts on endocortical bone surfaces is non-uniform, and we hypothesize that studying co-localization of in idual tumor cells with resident cell populations will reveal the identity of critical cellular components of the niche. In this study, we have mapped the distribution of three human prostate cancer cell lines (PC3-NW1, LN-CaP, and C4 2B4) colonizing the tibiae of athymic mice following intracardiac injection and evaluated their interaction with potential metastatic niches. Prostate cancer cells labeled with the fluorescent cell membrane dye (Vybrant DiD) were found by two-photon microscopy to be engrafted in the tibiae in close proximity (∼40 µm) to bone surfaces and 70% more cancer cells were detected in the lateral compared to the medial endocortical bone regions. This was associated with a 5-fold higher number of osteoblasts and 7-fold higher bone formation rate on the lateral endocortical bone surface compared to the medial side. By disrupting cellular interactions mediated by the chemokine (C-X-C motif) receptor 4 (CXCR4)/chemokine ligand 12 (CXCL12) axis with the CXCR4 inhibitor AMD3100, the preferential homing pattern of prostate cancer cells to osteoblast-rich bone surfaces was disrupted. In this study, we map the location of prostate cancer cells that home to endocortical regions in bone and our data demonstrate that homing of prostate cancer cells is associated with the presence and activity of osteoblast lineage cells, and suggest that therapies targeting osteoblast niches should be considered to prevent development of incurable prostate cancer bone metastases.
Publisher: Cold Spring Harbor Laboratory
Date: 11-06-2018
DOI: 10.1101/338863
Abstract: Osteoporosis is a common debilitating chronic disease diagnosed primarily using bone mineral density (BMD). We undertook a comprehensive assessment of human genetic determinants of bone density in 426,824 in iduals, identifying a total of 518 genome-wide significant loci, (301 novel), explaining 20% of the total variance in BMD—as estimated by heel quantitative ultrasound (eBMD). Next, meta-analysis identified 13 bone fracture loci in ~1.2M in iduals, which were also associated with BMD. We then identified target genes from cell-specific genomic landscape features, including chromatin conformation and accessible chromatin sites, that were strongly enriched for genes known to influence bone density and strength (maximum odds ratio = 58, P = 10 −75 ). We next performed rapid throughput skeletal phenotyping of 126 knockout mice lacking eBMD Target Genes and showed that these mice had an increased frequency of abnormal skeletal phenotypes compared to 526 unselected lines (P 0.0001). In-depth analysis of one such Target Gene, DAAM2 , showed a disproportionate decrease in bone strength relative to mineralization. This comprehensive human and murine genetic atlas provides empirical evidence testing how to link associated SNPs to causal genes, offers new insights into osteoporosis pathophysiology and highlights opportunities for drug development.
Publisher: Public Library of Science (PLoS)
Date: 14-09-2012
Publisher: Wiley
Date: 11-2006
DOI: 10.1111/J.1365-2141.2006.06356.X
Abstract: The effect of bortezomib on bone remodelling was evaluated in 34 relapsed myeloma patients. At baseline, patients had increased serum concentrations of dickkopf-1 (DKK-1), soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), sRANKL/osteoprotegerin ratio, C-telopeptide of type-I collagen (CTX) and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b) bone-alkaline phosphatase and osteocalcin were reduced. Serum DKK-1 correlated with CTX and severe bone disease. Bortezomib administration significantly reduced serum DKK-1, sRANKL, CTX, and TRACP-5b after four cycles, and dramatically increased bone-alkaline phosphatase and osteocalcin, irrespective of treatment response. This is the first study showing that bortezomib reduces DKK-1 and RANKL serum levels, leading to the normalisation of bone remodelling in relapsed myeloma.
Publisher: The Company of Biologists
Date: 02-2010
DOI: 10.1242/DEV.044164
Abstract: Although the regulation of osteoblast and adipocyte differentiation from mesenchymal stem cells has been studied for some time, very little is known about what regulates their appearance in discrete regions of the embryo. Here we show that, as in other vertebrates, zebrafish osteoblasts and adipocytes originate in part from cephalic neural crest (CNC) precursors. We investigated the roles that the retinoic acid (RA) and Peroxisome proliferator-activated receptor gamma (Pparg) pathways play in vivo and found that both pathways act on CNC to direct adipocyte differentiation at the expense of osteoblast formation. In addition, we identify two distinct roles for RA in the osteoblast lineage: an early role in blocking the recruitment of osteoblasts and a later role in mature osteoblasts to promote bone matrix synthesis. These findings might help to increase our understanding of skeletal and obesity-related diseases and aid in the development of stem cell-based regenerative therapies.
Publisher: Oxford University Press (OUP)
Date: 1991
Abstract: In order to establish the prevalence of osteomalacia in elderly patients with hip fracture, trans-iliac biopsies were obtained from 49 patients, aged 67-92 years, admitted to Cardiff Royal Infirmary with hip fracture. Undecalcified sections were quantitatively assessed and the diagnosis of osteomalacia was made when there was an increase in mean osteoid seam width (greater than 15 microns) associated with a reduction in calcification fronts (less than 60% of osteoid-covered surfaces). Osteomalacia was present in only one patient in the remaining patients, osteoid surface extent, volume and mean seam width were within normal limits. Thus osteomalacia, when defined by rigorous histomorphometric criteria, was rare in these elderly subjects with hip fracture.
Publisher: Springer Science and Business Media LLC
Date: 05-05-2021
DOI: 10.1038/S41467-021-22517-1
Abstract: Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders ( P = 2.4 × 10 −22 ) and are associated with the polygenic diseases osteoporosis ( P = 1.8 × 10 −13 ) and osteoarthritis ( P = 1.6 × 10 −7 ). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease.
Publisher: Elsevier BV
Date: 08-2009
Abstract: Bisphosphonates (BPs) prevent, reduce, and delay multiple myeloma (MM)-related skeletal complications. Intravenous pamidronate and zoledronic acid, and oral clodronate are used for the management of MM bone disease. The purpose of this paper is to review the current evidence for the use of BPs in MM and provide European Union-specific recommendations to support the clinical practice of treating myeloma bone disease. An interdisciplinary, expert panel of specialists on MM and myeloma-related bone disease convened for a face-to-face meeting to review and assess the evidence and develop the recommendations. The panel reviewed and graded the evidence available from randomized clinical trials, clinical practice guidelines, and the body of published literature. Where published data were weak or unavailable, the panel used their own clinical experience to put forward recommendations based solely on their expert opinions. The panel recommends the use of BPs in MM patients suffering from lytic bone disease or severe osteoporosis. Intravenous administration may be preferable however, oral administration can be considered for patients unable to make hospital visits. Dosing should follow approved indications with adjustments if necessary. In general, BPs are well tolerated, but preventive steps should be taken to avoid renal impairment and osteonecrosis of the jaw (ONJ). The panel agrees that BPs should be given for 2 years, but this may be extended if there is evidence of active myeloma bone disease. Initial therapy of ONJ should include discontinuation of BPs until healing occurs. BPs should be restarted if there is disease progression. BPs are an essential component of MM therapy for minimizing skeletal morbidity. Recent retrospective data indicate that a modified dosing regimen and preventive measures can greatly reduce the incidence of ONJ.
Publisher: Elsevier BV
Date: 2011
DOI: 10.1016/J.MOD.2010.11.006
Abstract: In tetrapod long bones, Hedgehog signalling is required for osteoblast differentiation in the perichondrium. In this work we analyse skeletogenesis in zebrafish larvae treated with the Hedgehog signalling inhibitor cyclopamine. We show that cyclopamine treatment leads to the loss of perichondral ossification of two bones in the head. We find that the Hedgehog co-receptors patched1 and patched2 are expressed in regions of the perichondrium that will form bone before the onset of ossification. We also show that cyclopamine treatment strongly reduces the expression of osteoblast markers in the perichondrium and that perichondral ossification is enhanced in patched1 mutant fish. This data suggests a conserved role for Hedgehog signalling in promoting perichondral osteoblast differentiation during vertebrate skeletal development. However, unlike what is seen during long bone development, we did not observe ectopic chondrocytes in the perichondrium when Hedgehog signalling is blocked. This result may point to subtle differences between the development of the skeleton in the skull and limb.
Publisher: Elsevier BV
Date: 09-2004
Publisher: Portland Press Ltd.
Date: 02-1999
DOI: 10.1042/BST0270224
Publisher: Cold Spring Harbor Laboratory
Date: 10-11-2019
DOI: 10.1101/836221
Abstract: Osteoarthritis causes debilitating pain and disability, resulting in a huge socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in unselected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1 , and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we generate mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by Crispr/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. This expanding resource of unselected mutant mice will transform the field by accelerating functional gene discovery in osteoarthritis and offering unanticipated drug discovery opportunities for this common and incapacitating chronic disease.
Publisher: Elsevier BV
Date: 05-1993
Publisher: Springer Science and Business Media LLC
Date: 15-04-2019
DOI: 10.1038/S41588-019-0415-X
Abstract: In the version of this article initially published, in Fig. 5a, the data in the right column of 'DAAM2 gRNA1' were incorrectly plotted as circles indicating 'untreated' rather than as squares indicating 'treated'. The error has been corrected in the HTML and PDF versions of the article.
Publisher: Springer Science and Business Media LLC
Date: 2010
DOI: 10.1186/AR3098
Publisher: Frontiers Media SA
Date: 04-07-2018
Publisher: Springer Science and Business Media LLC
Date: 03-12-2015
DOI: 10.1038/NCOMMS9983
Abstract: Multiple myeloma is largely incurable, despite development of therapies that target myeloma cell-intrinsic pathways. Disease relapse is thought to originate from dormant myeloma cells, localized in specialized niches, which resist therapy and repopulate the tumour. However, little is known about the niche, and how it exerts cell-extrinsic control over myeloma cell dormancy and reactivation. In this study, we track in idual myeloma cells by intravital imaging as they colonize the endosteal niche, enter a dormant state and subsequently become activated to form colonies. We demonstrate that dormancy is a reversible state that is switched ‘on’ by engagement with bone-lining cells or osteoblasts, and switched ‘off’ by osteoclasts remodelling the endosteal niche. Dormant myeloma cells are resistant to chemotherapy that targets iding cells. The demonstration that the endosteal niche is pivotal in controlling myeloma cell dormancy highlights the potential for targeting cell-extrinsic mechanisms to overcome cell-intrinsic drug resistance and prevent disease relapse.
Publisher: Birkhäuser Basel
Date: 2000
Publisher: Springer Science and Business Media LLC
Date: 18-09-2013
DOI: 10.1007/S00223-013-9794-7
Abstract: Tumor cells with high skeletal homing affinity express numerous cell surface receptors that bind ligands produced in bone. Upon arrival, these cells survive in the host environment, encompassed in close proximity to bone marrow cells. Interactions between tumor cells and cells of the host microenvironment are essential to not only tumor cell survival but also their activation and proliferation into environment-modifying tumors. Through the production of RANKL, PTHrP, cytokines, and integrins, activated tumor cells stimulate osteoclastogenesis, enhance bone resorption, and subsequently release matrix-bound proteins that further promote tumor growth and bone resorption. In addition, alterations in the TGF-β/BMP and Wnt signaling pathways via tumor cell growth can either stimulate or suppress osteoblastic bone formation and function, leading to sclerotic or lytic bone disease, respectively. Hence, the presence of tumor cells in bone dysregulates bone remodeling, dramatically impairing skeletal integrity. Furthermore, through complex mechanisms, cells of the immune system interact with tumor cells to further impact bone remodeling. Lastly, with alterations in bone cell activity, the environment is permissive to promoting tumor growth further, suggesting an interdependence between tumor cells and bone cells in metastatic bone disease and multiple myeloma.
Publisher: Wiley
Date: 10-2000
DOI: 10.1359/JBMR.2000.15.10.1935
Abstract: Multiple myeloma is associated with the development of osteolytic bone disease characterized by a disruption to normal bone resorption and bone formation. Although studies have shown that myeloma cells produce factors that promote bone resorption little data are available examining the mechanism of decreased bone formation or the factors that mediate this effect. In the present study we describe a novel in vitro coculture system in which to investigate the effect of myeloma cells on osteoblast recruitment and differentiation. Under appropriate conditions mesenchymal stem cells were shown to differentiate into colonies of cells, a proportion of which show characteristics of osteoblasts, in that they express alkaline phosphatase activity and stain positively for collagen and calcium. The addition of the human myeloma cells JJN-3, RPMI-8226, or NCI-H929 to these cultures stimulated a significant increase in the total number of colonies (p < 0.005) and the proportion of osteoblastic colonies (p < 0.005). Media conditioned by these cells also were able to promote the formation of both total and osteoblastic colonies (p < 0.005). The addition of an antibody against the interleukin-6 receptor (IL-6R) blocked myeloma cell and myeloma cell-conditioned media induced osteoblast recruitment (p < 0.01). Furthermore, media conditioned by myeloma cells incubated with phorbol ester, which promotes IL-6R shedding, or a metalloproteinase inhibitor, which inhibits IL-6R shedding, were able to stimulate (p < 0.005) and inhibit osteoblast recruitment (p < 0.005), respectively. In addition, soluble IL-6R (sIL-6R) and IL-6 together, but not alone, were able to promote osteoblastic colony formation (p < 0.01). Taken together these data show that myeloma cells promote osteoblast recruitment by release of sIL-6R from myeloma cells.
Publisher: Wiley
Date: 25-06-2019
DOI: 10.1002/JBMR.3744
Abstract: Expression of the vitamin D receptor (VDR) is thought to be associated with neoplastic progression. However, the role of the VDR in breast cancer metastasis to bone and the molecular mechanisms underlying this process are unknown. Employing a rodent model (female Balb/c nu/nu mice) of systemic metastasis, we here demonstrate that knockdown of the VDR strongly increases the metastatic potential of MDA‐MB‐231 human breast cancer cells to bone, resulting in significantly greater skeletal tumor burden. Ablation of VDR expression promotes cancer cell mobility (migration) and invasiveness, thereby facilitating skeletal colonization. Mechanistically, these changes in tumor cell behavior are attributable to shifts in the expression of proteins involved in cell adhesion, proliferation, and cytoskeletal organization, patterns characteristic for epithelial‐to‐mesenchymal cell transition (EMT). In keeping with these experimental findings, analyses of human breast cancer specimens corroborated the association between VDR expression, EMT‐typical changes in protein expression patterns, and clinical prognosis. Loss of the VDR in human breast cancer cells marks a critical point in oncogenesis by inducing EMT, promoting the dissemination of cancer cells, and facilitating the formation of tumor colonies in bone. © 2019 American Society for Bone and Mineral Research.
Publisher: Springer Berlin Heidelberg
Date: 2011
Publisher: American Society of Hematology
Date: 02-02-2021
DOI: 10.1182/BLOODADVANCES.2020002378
Abstract: An exploratory end point from a recent trial in patients with newly diagnosed multiple myeloma showed that median progression-free survival (PFS) was increased by 10.7 months with denosumab vs zoledronic acid. We performed additional analyses to identify factors that may have contributed to the favorable PFS with denosumab. Ad hoc analyses were performed for patients intending to undergo autologous stem cell transplantation (ASCT ASCT intent), not intending to undergo ASCT (ASCT no intent), and intent-to-treat according to age (& or ≥70 years) and baseline renal function (≤60 mL/min or & mL/min creatinine clearance [CrCl]). Of 1718 patients, 930 (54.1%) were in the ASCT-intent subgroup, and 788 (45.9%) were in the ASCT-no-intent subgroup. In the ASCT-intent subgroup, frontline triplet (median PFS, not estimable vs 35.7 months hazard ratio [HR] [95% confidence interval (CI)], 0.65 [0.47-0.90] descriptive P = .009) or bortezomib-only (median PFS, not estimable vs not estimable HR [95% CI], 0.61 [0.39–0.95] descriptive P = .029) induction regimens demonstrated the strongest PFS benefit favoring denosumab vs zoledronic acid. In the ASCT-no-intent subgroup, no benefit with denosumab vs zoledronic acid was observed. PFS favored denosumab vs zoledronic acid in patients with CrCl & mL/min and in patients & years old, but no difference was observed in patients with CrCl ≤60 mL/min or patients ≥70 years old. The PFS difference observed with denosumab is one of the notable benefits reported in newly diagnosed multiple myeloma and was most pronounced in patients intending to undergo ASCT and those who received proteasome inhibitor (PI)−based triplet regimens. This study was registered at www.clinicaltrials.gov as #NCT01345019.
Publisher: Elsevier BV
Date: 06-1997
Abstract: ADAMs (A disintegrin and metalloproteinase) are a recently discovered family of proteins with significant primary sequence similarity to the reprolysin family of snake venomases. These ADAMs closest known homologues are the type III reprolysin enzymes which have been demonstrated to be, among other things potent type IV collagenases. ADAMs are putative membrane linked proteins with several domains including a metalloproteinase domain, a potential integrin binding domain, a cysteine rich sequence and an EGF like sequence. They have been implicated in a wide variety of functions including basement membrane degradation and cell-cell and cell-matrix interactions. We have used RT-PCR and Northern blotting to characterise the expression of members of this family in cells derived from a variety of haematological malignancies including leukaemia (HL60 and Jurkat), erythroleukaemia (K562), lymphoma (U937 and Cupillo) and myeloma (U266B1). We find clear expression of four members of this novel family of proteins but note differences in the expression levels of each member. The ADAMs known as MADM (ADAM10), MCMP (ADAM12, MDC9) and Metargidin (ADAM15) which all possess potentially active metalloproteinase domains are expressed in all these cell types to significant levels. The putative tumour suppressor gene MDC (ADAM11) is expressed at very low levels in all cells examined. As ADAMs may have both potential metalloproteinase activity and adhesive domains we wish to explore the role of these proteins with regard to pathophysiology of haematological malignancy such as egression of leukaemic cells from the bone marrow.
Publisher: Public Library of Science (PLoS)
Date: 13-08-2012
Publisher: Springer Science and Business Media LLC
Date: 11-2006
DOI: 10.1007/S10585-006-9038-6
Abstract: Multiple myeloma (MM) is a plasma cell malignancy, characterized by the localization of the MM cells in the bone marrow (BM), where they proliferate and induce osteolysis. The MM cells first need to home or migrate to the BM to receive necessary survival signals. In this work, we studied the role of CCR1 and CCR5, two known chemokine receptors, in both chemotaxis and osteolysis in the experimental 5TMM mouse model. A CCR1-specific (BX471) and a CCR5-specific (TAK779) antagonist were used to identify the function of both receptors. We could detect by RT-PCR and flow cytometric analyses the expression of both CCR1 and CCR5 on the cells and their major ligand, macrophage inflammatory protein 1alpha (MIP1alpha) could be detected by ELISA. In vitro migration assays showed that MIP1alpha induced a 2-fold increase in migration of 5TMM cells, which could only be blocked by TAK779. In vivo homing kinetics showed a 30% inhibition in BM homing when 5TMM cells were pre-treated with TAK779. We found, in vitro, that both inhibitors were able to reduce osteoclastogenesis and osteoclastic resorption. In vivo end-term treatment of 5T2MM mice with BX471 resulted in a reduction of the osteolytic lesions by 40% while TAK779 treatment led to a 20% decrease in lesions. Furthermore, assessment of the microvessel density demonstrated a role for both receptors in MM induced angiogenesis. These data demonstrate the differential role of CCR1 and CCR5 in MM chemotaxis and MM associated osteolysis and angiogenesis.
Publisher: Wiley
Date: 08-03-2018
DOI: 10.1002/JBM4.10033
Publisher: Springer Science and Business Media LLC
Date: 22-02-2007
Abstract: The growth and survival of myeloma cells is critically regulated by cells of the bone marrow microenvironment, including osteoblasts. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of myeloma cell apoptosis, however, this antimyeloma activity is inhibited by osteoprotegerin (OPG) released from osteoblasts. Therefore, we hypothesized that specific agonists of TRAIL death receptors would not be inhibited by OPG released from osteoblasts and thus may represent a novel therapeutic approach in multiple myeloma. In the present study, TRAIL-induced apoptosis was demonstrated to be mediated through both DR4 and DR5. Specific agonist antibodies to DR4 or DR5 dose-dependently induced myeloma cell apoptosis, which was not prevented by OPG or by medium conditioned by osteoblasts. Co-culture of myeloma cells with osteoblasts protected against TRAIL-induced apoptosis of myeloma cells, and this protective effect was due to OPG. In contrast, the co-culture of myeloma cells with osteoblasts had no protective effect on apoptosis induced by specific agonists of DR4 or DR5. TRAIL has been proposed as a potential antitumour therapy, but within the bone marrow microenvironment OPG may interfere with the action of TRAIL. Specific agonists of TRAIL death receptors would not be subject to this inhibition and thus may provide an alternative specific antimyeloma therapy.
Publisher: Wiley
Date: 2007
DOI: 10.1002/IJC.22845
Abstract: During the last decade, a central role for insulin-like growth factor 1 (IGF-1) in the pathophysiology of multiple myeloma (MM) has been well established. IGF-I provided by the tumor-microenvironment interaction may directly and indirectly facilitate the migration, survival and expansion of the MM cells in the bone marrow (BM). The inhibition of the IGF-1R-mediated signaling pathway has recently been suggested to be a possible new therapeutic principle in MM. Using the mouse 5T2MM model, we now demonstrate that targeting the IGF-1R using picropodophyllin (PPP) in a therapeutical setting not only has strong antitumor activity on the established MM tumor but also influences the BM microenvironment by inhibiting angiogenesis and bone disease, having a profound effect on the survival of the mice. At therapeutically achievable concentrations of PPP, the average survival was 180 days for the PPP-treated mice as compared to 100 days for vehicle-treated mice. PPP used as single drug treatment in the 5T2MM model resulted in a decrease of tumor burden by 65% while the paraprotein concentrations were reduced by 75%. This decrease was associated with a significant inhibition of tumor-associated angiogenesis and osteolysis. The present studies on the biological effects of PPP in the 5T2MM model constitute an important experimental platform for future therapeutic implementation.
Publisher: Wiley
Date: 23-11-2010
DOI: 10.1002/JBMR.142
Abstract: Cancers that grow in bone, such as myeloma and breast cancer metastases, cause devastating osteolytic bone destruction. These cancers hijack bone remodeling by stimulating osteoclastic bone resorption and suppressing bone formation. Currently, treatment is targeted primarily at blocking bone resorption, but this approach has achieved only limited success. Stimulating osteoblastic bone formation to promote repair is a novel alternative approach. We show that a soluble activin receptor type IIA fusion protein (ActRIIA.muFc) stimulates osteoblastogenesis (p < .01), promotes bone formation (p < .01) and increases bone mass in vivo (p < .001). We show that the development of osteolytic bone lesions in mice bearing murine myeloma cells is caused by both increased resorption (p < .05) and suppression of bone formation (p < .01). ActRIIA.muFc treatment stimulates osteoblastogenesis (p < .01), prevents myeloma-induced suppression of bone formation (p < .05), blocks the development of osteolytic bone lesions (p < .05), and increases survival (p < .05). We also show, in a murine model of breast cancer bone metastasis, that ActRIIA.muFc again prevents bone destruction (p < .001) and inhibits bone metastases (p < .05). These findings show that stimulating osteoblastic bone formation with ActRIIA.muFc blocks the formation of osteolytic bone lesions and bone metastases in models of myeloma and breast cancer and paves the way for new approaches to treating this debilitating aspect of cancer.
Publisher: Wiley
Date: 07-07-2003
DOI: 10.1034/J.1600-065X.2003.00035.X
Abstract: Multiple myeloma (MM) is a B cell neoplasm characterized by the monoclonal proliferation of plasma cells in the bone marrow, the development of osteolytic lesions and the induction of angiogenesis. These different processes require three-dimensional interactions, with both humoral and cellular contacts. The 5TMM models are suitable models to study these interactions. These murine models originate from spontaneously developed myeloma in elderly mice, which are propagated by in vivo transfer of the myeloma cells into young syngeneic mice. In this review we report on studies performed in the 5TMM models with special emphasis on the homing of the myeloma cells, the characterization of the migrating and proliferating clone and the identification of the isotype switch variants. The bone marrow microenvironment was further targeted with osteoprotegerin (OPG) to block the RANK/RANKL/OPG system and with potent bisphosphonates. Both treatments resulted in a significant protection against myeloma-associated bone disease, and they decreased myeloma disease, as evidenced by a lower tumor load and an increased survival of the mice. These different studies demonstrate the strength of these models, not only in unraveling basic biological processes but also in the testing of potentially new therapeutic targets.
Publisher: American Society of Hematology
Date: 04-07-2019
Abstract: The era of targeted therapies has seen significant improvements in depth of response, progression-free survival, and overall survival for patients with multiple myeloma. Despite these improvements in clinical outcome, patients inevitably relapse and require further treatment. Drug-resistant dormant myeloma cells that reside in specific niches within the skeleton are considered a basis of disease relapse but remain elusive and difficult to study. Here, we developed a method to sequence the transcriptome of in idual dormant myeloma cells from the bones of tumor-bearing mice. Our analyses show that dormant myeloma cells express a distinct transcriptome signature enriched for immune genes and, unexpectedly, genes associated with myeloid cell differentiation. These genes were switched on by coculture with osteoblastic cells. Targeting AXL, a gene highly expressed by dormant cells, using small-molecule inhibitors released cells from dormancy and promoted their proliferation. Analysis of the expression of AXL and coregulated genes in human cohorts showed that healthy human controls and patients with monoclonal gammopathy of uncertain significance expressed higher levels of the dormancy signature genes than patients with multiple myeloma. Furthermore, in patients with multiple myeloma, the expression of this myeloid transcriptome signature translated into a twofold increase in overall survival, indicating that this dormancy signature may be a marker of disease progression. Thus, engagement of myeloma cells with the osteoblastic niche induces expression of a suite of myeloid genes that predicts disease progression and that comprises potential drug targets to eradicate dormant myeloma cells.
Publisher: Elsevier BV
Date: 12-2017
Publisher: Springer Science and Business Media LLC
Date: 22-08-2018
DOI: 10.1038/S41467-018-05772-7
Abstract: Vaccine-induced immunity depends on the generation of memory B cells (MBC). However, where and how MBCs are reactivated to make neutralising antibodies remain unknown. Here we show that MBCs are prepositioned in a subcapsular niche in lymph nodes where, upon reactivation by antigen, they rapidly proliferate and differentiate into antibody-secreting plasma cells in the subcapsular proliferative foci (SPF). This novel structure is enriched for signals provided by T follicular helper cells and antigen-presenting subcapsular sinus macrophages. Compared with contemporaneous secondary germinal centres, SPF have distinct single-cell molecular signature, cell migration pattern and plasma cell output. Moreover, SPF are found both in human and mouse lymph nodes, suggesting that they are conserved throughout mammalian evolution. Our data thus reveal that SPF is a seat of immunological memory that may be exploited to rapidly mobilise secondary antibody responses and improve vaccine efficacy.
Publisher: Wiley
Date: 08-2015
DOI: 10.1096/FJ.14-266379
Abstract: This study aimed to identify subpopulations of prostate cancer cells that are responsible for the initiation of bone metastases. Using rapidly iding human prostate cancer cell lines, we identified mitotically quiescent subpopulations (<1%), which we compared with the rapidly iding populations for patterns of gene expression and for their ability to migrate to the skeletons of athymic mice. The study used 2-photon microscopy to map the presence/distribution of fluorescently labeled, quiescent cells and luciferase expression to determine the presence of growing bone metastases. We showed that the mitotically quiescent cells were very significantly more tumorigenic in forming bone metastases than fast-growing cells (55 vs. 15%) and had a unique gene expression profile. The quiescent cells were not uniquely stem cell like, with no expression of CD133 but had the same level expression of other putative prostate stem cell markers (CD44 and integrins α2/β1), when compared to the rapidly proliferating population. In addition, mitotic quiescence was associated with very high levels of C-X-C chemokine receptor type 4 (CXCR4) production. Inhibition of CXCR4 activity altered the homing of quiescent tumor cells to bone. Our studies suggest that mitotic dormancy is a unique phenotype that facilitates tumor cell colonization of the skeleton in prostate cancer.
Publisher: Wiley
Date: 23-01-2012
DOI: 10.1002/JBMR.547
Abstract: Progeny of mice treated with the mutagen N-ethyl-N-nitrosourea (ENU) revealed a mouse, designated Longpockets (Lpk), with short humeri, abnormal vertebrae, and disorganized growth plates, features consistent with spondyloepiphyseal dysplasia congenita (SEDC). The Lpk phenotype was inherited as an autosomal dominant trait. Lpk/+ mice were viable and fertile and Lpk/Lpk mice died perinatally. Lpk was mapped to chromosome 15 and mutational analysis of likely candidates from the interval revealed a Col2a1 missense Ser1386Pro mutation. Transient transfection of wild-type and Ser1386Pro mutant Col2a1 c-Myc constructs in COS-7 cells and CH8 chondrocytes demonstrated abnormal processing and endoplasmic reticulum retention of the mutant protein. Histology revealed growth plate disorganization in 14-day-old Lpk/+ mice and embryonic cartilage from Lpk/+ and Lpk/Lpk mice had reduced safranin-O and type-II collagen staining in the extracellular matrix. The wild-type and Lpk/+ embryos had vertical columns of proliferating chondrocytes, whereas those in Lpk/Lpk mice were perpendicular to the direction of bone growth. Electron microscopy of cartilage from 18.5 dpc wild-type, Lpk/+, and Lpk/Lpk embryos revealed fewer and less elaborate collagen fibrils in the mutants, with enlarged vacuoles in the endoplasmic reticulum that contained amorphous inclusions. Micro-computed tomography (CT) scans of 12-week-old Lpk/+ mice revealed them to have decreased bone mineral density, and total bone volume, with erosions and osteophytes at the joints. Thus, an ENU mouse model with a Ser1386Pro mutation of the Col2a1 C-propeptide domain that results in abnormal collagen processing and phenotypic features consistent with SEDC and secondary osteoarthritis has been established.
Publisher: The Endocrine Society
Date: 15-06-2017
Publisher: Bioscientifica
Date: 10-2016
DOI: 10.1530/JOE-16-0258
Abstract: The genetic determinants of osteoporosis remain poorly understood, and there is a large unmet need for new treatments in our ageing society. Thus, new approaches for gene discovery in skeletal disease are required to complement the current genome-wide association studies in human populations. The International Knockout Mouse Consortium (IKMC) and the International Mouse Phenotyping Consortium (IMPC) provide such an opportunity. The IKMC generates knockout mice representing each of the known protein-coding genes in C57BL/6 mice and, as part of the IMPC initiative, the Origins of Bone and Cartilage Disease project identifies mutants with significant outlier skeletal phenotypes. This initiative will add value to data from large human cohorts and provide a new understanding of bone and cartilage pathophysiology, ultimately leading to the identification of novel drug targets for the treatment of skeletal disease.
Publisher: Wiley
Date: 23-03-2011
DOI: 10.1002/JBMR.266
Abstract: Small molecules are attractive therapeutics to lify and direct differentiation of stem cells. They also can be used to understand the regulation of their fate by interfering with specific signaling pathways. Mesenchymal stem cells (MSCs) have the potential to proliferate and differentiate into several cell types, including osteoblasts. Activation of canonical Wnt signaling by inhibition of glycogen synthase kinase 3 (GSK-3) has been shown to enhance bone mass, possibly by involving a number of mechanisms ranging from lification of the mesenchymal stem cell pool to the commitment and differentiation of osteoblasts. Here we have used a highly specific novel inhibitor of GSK-3, AR28, capable of inducing β-catenin nuclear translocation and enhanced bone mass after 14 days of treatment in BALB/c mice. We have shown a temporally regulated increase in the number of colony-forming units-osteoblast (CFU-O) and -adipocyte (CFU-A) but not colony-forming units-fibroblast (CFU-F) in mice treated for 3 days. However, the number of CFU-O and CFU-A returned to normal levels after 14 days of treatment, and the number of CFU-F was decreased significantly. In contrast, the number of osteoblasts increased significantly only after 14 days of treatment, and this was seen together with a significant decrease in bone marrow adiposity. These data suggest that the increased bone mass is the result of an early temporal wave of lification of a subpopulation of MSCs with both osteogenic and adipogenic potential, which is driven to osteoblast differentiation at the expense of adipogenesis.
Publisher: Elsevier BV
Date: 07-2019
Publisher: Wiley
Date: 19-03-2019
DOI: 10.1002/JBMR.3691
Publisher: American Society of Hematology
Date: 29-06-2017
DOI: 10.1182/BLOOD-2017-03-773341
Abstract: Anti-sclerostin treatment increases bone mass and fracture resistance in MM Anti-sclerostin in combination with zoledronic acid is superior to zoledronic acid alone in increasing fracture resistance.
Publisher: Elsevier BV
Date: 05-2019
Publisher: Wiley
Date: 12-2012
DOI: 10.1002/9780470942390.MO120124
Abstract: The availability of high‐throughput biochemical and imaging techniques that can be used on live mice has increased the possibility of undertaking longitudinal studies to characterize skeletal changes such as bone mineral content and density. Further characterization of bone morphology, bone quality, and bone strength can also be achieved by analyzing dissected bones using techniques that provide higher resolution. Thus, the combined use of high‐throughput [e.g., biochemical analysis of plasma, radiography and dual‐energy X‐ray absorptiometry (DEXA)] and secondary phenotyping techniques (e.g., histology, histomorphometry, Faxitron digital X‐ray point projection microradiography, biomechanical testing, and micro‐computed tomography) can be utilized for comprehensive characterization of bone structure and quality and to elucidate the underlying molecular mechanisms giving rise to musculoskeletal disorders. Curr. Protoc. Mouse Biol . 2:365‐400 © 2012 by John Wiley & Sons, Inc.
Publisher: Elsevier BV
Date: 08-2004
Publisher: The Endocrine Society
Date: 09-2015
DOI: 10.1210/EN.2014-1943
Abstract: The ancestral glycoprotein hormone thyrostimulin is a heterodimer of unique glycoprotein hormone subunit alpha (GPA)2 and glycoprotein hormone subunit beta (GPB)5 subunits with high affinity for the TSH receptor. Transgenic overexpression of GPB5 in mice results in cranial abnormalities, but the role of thyrostimulin in bone remains unknown. We hypothesized that thyrostimulin exerts paracrine actions in bone and determined: 1) GPA2 and GPB5 expression in osteoblasts and osteoclasts, 2) the skeletal consequences of thyrostimulin deficiency in GPB5 knockout (KO) mice, and 3) osteoblast and osteoclast responses to thyrostimulin treatment. Gpa2 and Gpb5 expression was identified in the newborn skeleton but declined rapidly thereafter. GPA2 and GPB5 mRNAs were also expressed in primary osteoblasts and osteoclasts at varying concentrations. Juvenile thyrostimulin-deficient mice had increased bone volume and mineralization as a result of increased osteoblastic bone formation. However, thyrostimulin failed to induce a canonical cAMP response or activate the noncanonical Akt, ERK, or mitogen-activated protein kinase (P38) signaling pathways in primary calvarial or bone marrow stromal cell-derived osteoblasts. Furthermore, thyrostimulin did not directly inhibit osteoblast proliferation, differentiation or mineralization in vitro. These studies identify thyrostimulin as a negative but indirect regulator of osteoblastic bone formation during skeletal development.
Publisher: Springer Science and Business Media LLC
Date: 31-12-2018
Publisher: Wiley
Date: 18-07-2006
DOI: 10.1002/IJC.22033
Abstract: Dickkopf-1 (DKK-1) protein, a soluble inhibitor of Wnt signalling, has been implicated in the pathogenesis of myeloma bone disease through the suppression of osteoblast differentiation. In this study, serum concentrations of DKK-1 were measured in 50 myeloma patients (32 at diagnosis and 18 before and after autologous stem cell transplantation (ASCT), 18 patients with monoclonal gammopathy of undetermined significance (MGUS), and 22 healthy controls. Serum DKK-1 levels were increased in MM at diagnosis compared with MGUS (mean +/- SD: 67 +/- 54 ng/mL vs. 38 +/- 13 ng/mL p = 0.006) and controls (31 +/- 11 ng/mL p = 0.02), while there was no difference between MGUS patients and controls. Although patients with stage 2 and 3 myeloma had higher DKK-1 values than stage 1 patients (79 +/- 63 vs. 40 +/- 13 p = 0.005), no significant correlation between serum DKK-1 and myeloma bone disease was observed. Myeloma patients before ASCT also had increased levels of DKK-1 (63 +/- 77 ng/mL p = 0.03) compared with controls, supporting the notion that DKK-1 may be responsible for the suppressed osteoblast activity even in patients with low tumor burden. After ASCT, there was a sustained decrease in DKK-1 levels over time, while bone formation markers elevated, suggesting that the reduction of DKK-1 levels after ASCT may correlate with the normalization of osteoblast function. These results could provide the basis for developing agents that block DKK-1, thus restoring osteoblast function and counteracting the increased osteoclastogenesis observed in myeloma.
Publisher: Springer Science and Business Media LLC
Date: 1989
DOI: 10.1007/BF02556655
Publisher: Elsevier BV
Date: 2008
Publisher: MDPI AG
Date: 26-09-2018
DOI: 10.3390/IJMS19102920
Abstract: Breast cancer cells colonize the skeleton by homing to specific niches, but the involvement of osteoblasts in tumour cell seeding, colonization, and progression is unknown. We used an in vivo model to determine how increasing the number of cells of the osteoblast lineage with parathyroid hormone (PTH) modified subsequent skeletal colonization by breast cancer cells. BALB/c nude mice were injected for five consecutive days with PBS (control) or PTH and then injected with DiD-labelled breast cancer cells via the intra-cardiac route. Effects of PTH on the bone microenvironment and tumour cell colonization and growth was analyzed using bioluminescence imaging, two-photon microscopy, and histological analysis. PTH treatment caused a significant, transient increase in osteoblast numbers compared to control, whereas bone volume/structure in the tibia was unaffected. There were no differences in the number of tumour cells seeding to the tibias, or in the number of tumours in the hind legs, between the control and PTH group. However, animals pre-treated with PTH had a significantly higher number of tumour colonies distributed throughout skeletal sites outside the hind limbs. This is the first demonstration that PTH-induced stimulation of osteoblastic cells may result in alternative skeletal sites becoming available for breast cancer cell colonization.
Publisher: Wiley
Date: 03-2003
DOI: 10.1359/JBMR.2003.18.3.482
Abstract: Multiple myeloma is characterized by the growth of plasma cells in the bone marrow and the development of osteolytic bone disease. Myeloma cells are found closely associated with bone, and targeting this environment may therefore affect both the bone disease and the growth of myeloma cells. We have investigated the effect of the potent bisphosphonate, zoledronic acid, on the development of bone disease, tumor burden, and disease-free survival in the 5T2MM model of myeloma. 5T2MM murine myeloma cells were injected intravenously into C57BL/KaLwRij mice. After 8 weeks, all animals had a paraprotein. Animals were treated with zoledronic acid (120 microg/kg, subcutaneously, twice weekly) or vehicle, from the time of tumor cell injection or from paraprotein detection for 12 or 4 weeks, respectively. All animals injected with tumor cells developed osteolytic lesions, a decrease in cancellous bone volume, an increase in osteoclast perimeter, and a decrease in bone mineral density. Zoledronic acid prevented the formation of lesions, prevented cancellous bone loss and loss of bone mineral density, and reduced osteoclast perimeter. Zoledronic acid also decreased paraprotein concentration, decreased tumor burden, and reduced angiogenesis. In separate experiments, Kaplan-Meier analysis demonstrated a significant increase in survival after treatment with zoledronic acid when compared with control (47 vs. 35 days). A single dose of zoledronic acid was also shown to be effective in preventing the development of osteolytic bone disease. These data show that zoledronic acid is able to prevent the development of osteolytic bone disease, decrease tumor burden in bone, and increase survival in a model of established myeloma.
Publisher: Elsevier BV
Date: 07-1996
DOI: 10.1016/8756-3282(96)00108-1
Abstract: Menopausal bone loss is associated with disruption of cancellous bone architecture which has adverse mechanical effects and is believed to be irreversible. The aim of this study was to examine the effects of long-term hormone replacement therapy on cancellous bone structure in women with postmenopausal osteoporosis. Iliac crest biopsies from 22 women with osteopenia or osteoporosis were obtained before and after hormone replacement therapy (mean duration 23.5 months). Cancellous bone architecture was assessed by strut analysis, trabecular bone pattern factor, and marrow star volume. Post-treatment biopsies showed no significant changes in any of the structural indices assessed. Our results suggest that hormone replacement therapy preserves existing cancellous bone structure but provide no evidence that this treatment is able to reverse structural disruption in women with postmenopausal osteopenia or osteoporosis.
Publisher: Elsevier BV
Date: 07-1989
DOI: 10.1016/0169-6009(89)90039-1
Abstract: The relationship between trabecular thinning and loss of connectedness of the trabecular bone pattern has been studied in iliac crest bone s les from 89 normal subjects in order to determine the structural mechanisms underlying age-related bone loss. Trabecular width and structure were quantitatively assessed using computerized techniques. Highly significant negative correlations were found between the mean trabecular plate thickness and number of free ends/mm2 both in males (r = -0.571) and in females (r = -0.667) (P less than 0.001). Mean trabecular plate thickness also showed significant negative correlations with other structural indices indicating reduced connectedness, whereas positive correlations were found with those indices representing preservation of connectedness. Examination of the relative frequency of trabecular widths less than 100 microns revealed that only 2-5% of the trabecular surface would be susceptible to erosion by a resorption cavity of normal depth. These results indicate that trabecular thinning and erosion are interdependent processes in age-related bone loss. Since only a small percentage of the trabecular surface is susceptible to erosion, and resorption cavities normally occupy only 1-5% of the total trabecular surface, these findings imply that the site of activation of new BMUs may not be randomly distributed but may instead be preferentially located at sites of lower trabecular width.
Publisher: Elsevier BV
Date: 04-2021
Publisher: American Association for Cancer Research (AACR)
Date: 2015
DOI: 10.1158/2159-8290.CD-14-0621
Abstract: Recent clinical trials have shown that bisphosphonate drugs improve breast cancer patient survival independent of their antiresorptive effects on the skeleton. However, because bisphosphonates bind rapidly to bone mineral, the exact mechanisms of their antitumor action, particularly on cells outside of bone, remain unknown. Here, we used real-time intravital two-photon microscopy to show extensive leakage of fluorescent bisphosphonate from the vasculature in 4T1 mouse mammary tumors, where it initially binds to areas of small, granular microcalcifications that are engulfed by tumor-associated macrophages (TAM), but not tumor cells. Importantly, we also observed uptake of radiolabeled bisphosphonate in the primary breast tumor of a patient and showed the resected tumor to be infiltrated with TAMs and to contain similar granular microcalcifications. These data represent the first compelling in vivo evidence that bisphosphonates can target cells in tumors outside the skeleton and that their antitumor activity is likely to be mediated via TAMs. Significance: Bisphosphonates are assumed to act solely in bone. However, mouse models and clinical trials show that they have surprising antitumor effects outside bone. We provide unequivocal evidence that bisphosphonates target TAMs, but not tumor cells, to exert their extraskeletal effects, offering a rationale for use in patients with early disease. Cancer Discov 5(1) 35–42. ©2014 AACR. See related commentary by Sterling, p. 14 This article is highlighted in the In This Issue feature, p. 1
Publisher: Elsevier BV
Date: 06-2010
DOI: 10.1016/J.LEUKRES.2009.10.016
Abstract: We assessed the expression pattern and clinical relevance of BMPs and related molecules in multiple myeloma (MM). MM bone-marrow s les (n=32) had increased BMP4, BMP6, ACVR1 and ACVR2A, and decreased NOG expression compared with controls (n=15), with BMP6 having the highest sensitivity/specificity. Within MM bone-marrow, the source of BMPs was mainly CD138(+) plasma-cell population, and BMP6 and ACVR1 expression correlated with plasma-cell percentage. Using myeloma cell lines NCI H929 and Thiel we showed that BMPs induced ID1, ID2 and IL6, and suppressed CDKN1A and BAX gene expression, and BAX protein expression. Finally, BMPs partially protected myeloma cells from bortezomib- and TRAIL-induced apoptosis. We concluded that BMPs may be involved in MM pathophysiology and serve as myeloma cell biomarkers.
Publisher: Springer Science and Business Media LLC
Date: 25-05-2016
DOI: 10.1038/NRC.2016.44
Abstract: During the past decade preclinical studies have defined many of the mechanisms used by tumours to hijack the skeleton and promote bone metastasis. This has led to the development and widespread clinical use of bone-targeted drugs to prevent skeletal-related events. This understanding has also identified a critical dependency between colonizing tumour cells and the cells of bone. This is particularly important when tumour cells first arrive in bone, adapt to their new microenvironment and enter a long-lived dormant state. In this Review, we discuss the role of different bone cell types in supporting disseminated tumour cell dormancy and reactivation, and highlight the new opportunities this provides for targeting the bone microenvironment to control dormancy and bone metastasis.
Publisher: Wiley
Date: 31-07-2014
DOI: 10.1111/BJH.13020
Abstract: Defects in bone repair contribute to multiple myeloma (MM) bone disease. It is unknown whether this reflects failure of osteogenic differentiation from mesenchymal stromal cells (MSC), inherent stromal defects or mature cell dysfunction. We quantified the number of fibroblast colony-forming units (CFU-f) and osteoblast colony-forming units (CFU-ob) in freshly isolated bone marrow (BM) from healthy in iduals (N = 10) and MM patients (N = 54). CFU-f and CFU-ob were present in MM BM, at comparable frequency to normal subjects, irrespective of disease stage, and the presence of bone disease. Adherent cultures from MM BM are able to differentiate into osteoblasts, as indicated by the early upregulation of RUNX2, SP7, AXIN2 and DLX5, and the production of alkaline phosphatase and calcium. Coculture with MM cells failed to prevent osteogenic differentiation of adult human MSC. On the other hand, MM cells induced cell cycle progression in resting MSC in a cell contact dependent manner. This effect was confirmed using both primary CD138+ cells and MM cell lines, and was not seen with B or T cell lines. Our data confirm the presence of osteoblast progenitors and the preservation of osteogenic function in MM, however dysregulation of cell cycle control may contribute to the loss of normal bone homeostasis that ultimately results in osteolytic bone loss.
Publisher: American Association for Cancer Research (AACR)
Date: 2007
DOI: 10.1158/0008-5472.CAN-06-1287
Abstract: Multiple myeloma is a B-cell malignancy characterized by the uncontrolled growth of plasma cells in the bone marrow and the development of osteolytic bone disease. Myeloma cells express the receptor activator of nuclear factor κB ligand (RANKL), induce RANKL expression in the bone marrow, and down-regulate expression of the decoy receptor osteoprotegerin, thereby promoting bone resorption. Targeting this system in myeloma has clear therapeutic potential. However, osteoprotegerin also binds tumor necrosis factor–related apoptosis inducing ligand (TRAIL) and prevents TRAIL-induced apoptosis of myeloma cells. Whether or not osteoprotegerin can bind TRAIL and prevent apoptosis in vivo and the relative importance of osteoprotegerin binding to TRAIL and RANKL are unclear. In the present study, we have investigated the ability of an osteoprotegerin-like peptidomimetic (OP3-4), designed to block the RANKL/RANK interaction, to inhibit osteoclastic bone resorption and TRAIL-induced apoptosis in vitro and myeloma bone disease in vivo. OP3-4 inhibited osteoclast formation (P & 0.01) and bone resorption (P & 0.01) in vitro. However, OP3-4 had no effect on TRAIL-induced apoptosis of RPMI 8226 myeloma cells. Treatment of 5T2MM myeloma–bearing mice with OP3-4 decreased osteoclast number and the proportion of bone surface covered by osteoclasts (P & 0.05). Treatment also prevented the tumor-induced decrease in cancellous bone area and the development of osteolytic lesions (P & 0.05). OP3-4 also reduced tumor burden when compared with the control (P & 0.05). These data suggest that OP3-4 and the selective inhibition of RANKL, but not TRAIL activity, are effective in preventing myeloma bone disease and offer a novel therapeutic approach to treating this aspect of myeloma. [Cancer Res 2007 (1):202–8]
Publisher: Elsevier BV
Date: 07-2015
Publisher: Springer Science and Business Media LLC
Date: 04-1999
DOI: 10.1007/PL00004164
Publisher: Elsevier BV
Date: 02-1995
DOI: 10.1016/8756-3282(94)00038-2
Abstract: The administration of gonadotrophin-releasing hormone (GnRH) analogs to premenopausal women causes hypoestrogenism and bone loss, but the effects on cancellous microstructure have not been determined. In this study we have assessed bone structure in transiliac biopsies obtained from women before and after treatment for endometriosis with GnRH analogs. Twenty-one premenopausal women were studied, paired biopsies being obtained in 13 five women received both GnRH analogs and Org OD 14 (Tibolone, Livial). Comparison of pre- and post-treatment biopsies in women treated only with GnRH analogs showed a reduction in indices related to connectivity (node-to-terminus ratio, node-to-loop strut length, p < 0.02) and increase in inversely related indices (terminus-to-terminus and node-to-terminus strut length, p < 0.03). No significant changes were seen in any of the structural indices in women receiving both GnRH and Org OD 14 therapy. Activation frequency and bone formation rate at tissue level increased in women treated with GnRH agonists alone, although this change was not statistically significant. Our results suggest that bone loss induced by GnRH analogs may be associated with adverse effects on cancellous microstructure which are unlikely to be reversed following cessation of therapy. Concurrent treatment with Org OD 14 appears to prevent these changes.
Publisher: Wiley
Date: 07-1996
Abstract: Cancellous bone architecture is an important determinant of bone strength. Recently, several approaches to the assessment of bone structure in histological sections have been described however, no comparative studies of these different methods have been reported. We have developed computerized methods for the simultaneous assessment of several indices of bone structure, including trabecular bone pattern factor, marrow space star volume, node-to-terminus ratio, trabecular number, and trabecular separation. The relationships between these variables has been examined in iliac crest cancellous bone obtained from 41 healthy subjects, 17 male and 24 female, aged 20-80 years (mean 47.9 years). All structural indices assessed showed significant correlations with cancellous bone area (p < 0.0001). Values for trabecular bone pattern factor and marrow space volume were highly correlated (r = 0.789 p < 0.0001). A comparison of indices obtained by strut analysis with trabecular bone pattern factor and marrow space star volume also revealed significant relationships, especially for the terminus-to-terminus strut length (r = 0.704 and r = 0.634, respectively p < 0.0001) and node to terminus ratio (r = -0.947 and r = -0.788, respectively p < 0.0001). The node-to-terminus ratio and trabecular bone pattern factor showed significant relationships with age which were independent of sex, cancellous bone area and trabecular width (p < 0.01 and p < 0.005, respectively). Our results demonstrate strong correlations between the different two-dimensional indices of bone structure in cancellous bone from healthy subjects. Trabecular penetration is likely to be an important determinant of all these variables, which may therefore reflect connectivity however, direct comparison of these methods with three-dimensional techniques is required to establish their true relationship to bone structure.
Publisher: Proceedings of the National Academy of Sciences
Date: 03-07-2012
Abstract: Diseases such as osteoporosis are associated with reduced bone mass. Therapies to prevent bone loss exist, but there are few that stimulate bone formation and restore bone mass. Bone morphogenetic proteins (BMPs) are members of the TGFβ superfamily, which act as pleiotropic regulators of skeletal organogenesis and bone homeostasis. Ablation of the BMPR1A receptor in osteoblasts increases bone mass, suggesting that inhibition of BMPR1A signaling may have therapeutic benefit. The aim of this study was to determine the skeletal effects of systemic administration of a soluble BMPR1A fusion protein (mBMPR1A–mFc) in vivo. mBMPR1A–mFc was shown to bind BMP2/4 specifically and with high affinity and prevent downstream signaling. mBMPR1A–mFc treatment of immature and mature mice increased bone mineral density, cortical thickness, trabecular bone volume, thickness and number, and decreased trabecular separation. The increase in bone mass was due to an early increase in osteoblast number and bone formation rate, mediated by a suppression of Dickkopf-1 expression. This was followed by a decrease in osteoclast number and eroded surface, which was associated with a decrease in receptor activator of NF-κB ligand (RANKL) production, an increase in osteoprotegerin expression, and a decrease in serum tartrate-resistant acid phosphatase (TRAP5b) concentration. mBMPR1A treatment also increased bone mass and strength in mice with bone loss due to estrogen deficiency. In conclusion, mBMPR1A–mFc stimulates osteoblastic bone formation and decreases bone resorption, which leads to an increase in bone mass, and offers a promising unique alternative for the treatment of bone-related disorders.
Publisher: The Endocrine Society
Date: 16-05-2012
DOI: 10.1210/EN.2011-1814
Abstract: Calcineurin-nuclear factor of activated T cells signaling controls the differentiation and function of osteoclasts and osteoblasts, and regulator of calcineurin-2 (Rcan2) is a physiological inhibitor of this pathway. Rcan2 expression is regulated by T3, which also has a central role in skeletal development and bone turnover. To investigate the role of Rcan2 in bone development and maintenance, we characterized Rcan2−/− mice and determined its skeletal expression in T3 receptor (TR) knockout and thyroid-manipulated mice. Rcan2−/− mice had normal linear growth but displayed delayed intramembranous ossification, impaired cortical bone formation, and reduced bone mineral accrual during development as well as increased mineralization of adult bone. These abnormalities resulted from an isolated defect in osteoblast function and are similar to skeletal phenotypes of mice lacking the type 2 deiodinase thyroid hormone activating enzyme or with dominant-negative mutations of TRα, the predominant TR isoform in bone. Rcan2 mRNA was expressed in primary osteoclasts and osteoblasts, and its expression in bone was differentially regulated in TRα and TRβ knockout and thyroid-manipulated mice. However, in primary osteoblast cultures, T3 treatment did not affect Rcan2 mRNA expression or nuclear factor of activated T cells c1 expression and phosphorylation. Overall, these studies establish that Rcan2 regulates osteoblast function and its expression in bone is regulated by thyroid status in vivo.
Publisher: Elsevier BV
Date: 09-2004
Publisher: Wiley
Date: 10-2000
DOI: 10.1046/J.1365-2141.2000.02310.X
Abstract: Bisphosphonates are effective in the management of bone disease in patients with multiple myeloma and recent reports have suggested that they may also have an anti-tumour activity. In support of this, we have previously demonstrated that bisphosphonates can induce myeloma cell apoptosis in vitro however, it remains unclear whether this occurs in vivo. We have therefore investigated the effect of the potent bisphosphonate ibandronate in the 5T2MM murine model of established multiple myeloma. Short-term treatment with a high dose of ibandronate had no effect on either myeloma cell number or the proportion of myeloma cells undergoing apoptosis. These observations suggest that although bisphosphonates induce apoptosis in myeloma cells in vitro, they may not have the same anti-tumour effects in vivo.
Publisher: Public Library of Science (PLoS)
Date: 29-08-2012
Publisher: Springer Science and Business Media LLC
Date: 08-04-2013
DOI: 10.1038/APS.2012.182
Publisher: Springer Science and Business Media LLC
Date: 15-10-2020
Publisher: Wiley
Date: 17-08-2012
DOI: 10.1002/JBMR.1705
Publisher: Elsevier BV
Date: 02-1992
DOI: 10.1016/0169-6009(92)90884-G
Abstract: Using a computerised technique, resorption cavity characteristics in iliac crest trabecular bone were assessed in 30 patients with chronic renal failure and compared with data obtained from healthy subjects. The mean and maximum cavity depth were significantly greater in the patient group (P less than 0.0001) in addition, cavity area, the percentage of bone being remodelled, the number of cavities per mm trabecular surface and the percentage eroded surface were all significantly greater than in controls (P less than 0.0001). However, the surface length of in idual cavities in the patient group did not differ significantly from that of controls. In the patient group, serum intact parathyroid hormone concentrations showed a significant positive correlation with mean resorption cavity depth (r = 0.451, P less than 0.05). Our results demonstrate that the increase in bone resorption associated with hyperparathyroidism secondary to chronic renal failure is due to an increase both in the number and depth of cavities, although the surface extent of in idual cavities is normal. These findings indicate that factors determining the length of trabecular surface eroded and the depth of in idual resorption cavities are controlled by different mechanisms.
Publisher: Wiley
Date: 11-1999
Abstract: Bisphosphonates are chemically stable analogs of inorganic pyrophosphate, which are resistant to breakdown by enzymatic hydrolysis. The biological effects of bisphosphonates on calcium metabolism were originally ascribed to their physico-chemical effects on hydroxyapatite crystals. Although such effects may contribute to their overall action, their effects on cells are probably of greater importance, particularly for the more potent compounds. Remarkable progress has been made in increasing the potency of bisphosphonates as inhibitors of bone resorption, and the most potent compounds in current use are characterized by the presence of a nitrogen atom at critical positions in the side chain which, together with the bisphosphonate moiety itself, seems to be essential for maximal activity. As a class the bisphosphonates offer a very effective means of treating Paget's disease.
Publisher: Wiley
Date: 12-1989
DOI: 10.1111/J.1365-2265.1989.TB01291.X
Abstract: It has been postulated that secondary hyperparathyroidism contributes to bone loss and the high incidence of hip fractures in the elderly population, but there are no data on serum intact parathyroid hormone concentrations in these patients. In this study, serum intact parathyroid hormone (PTH) levels have been measured in 39 elderly patients with hip fracture in addition, serum 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 concentrations have been measured. Twenty patients (51.3%) had elevated serum intact PTH concentrations whilst five (12.8%) had abnormally low serum 25-hydroxyvitamin D3 levels and serum 1,25-dihydroxyvitamin D3 was reduced in only two. These results provide the first direct evidence for secondary hyperparathyroidism in elderly patients with hip fracture. Vitamin D deficiency is unlikely to be the sole cause of secondary hyperparathyroidism in these subjects and calcium deficiency by itself may also contribute.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
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