ORCID Profile
0000-0002-7757-6281
Current Organisations
Westmead Institute for Medical Research
,
Children's Hospital at Westmead
,
University of Sydney
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Chemical Engineering | Bioprocessing, Bioproduction and Bioproducts | Powder and Particle Technology | Food Engineering
ANZSRC Socio-Economic Objective (SEO)
Related Links
Publications
A combination of rhBMP-2 (recombinant human Bone Morphogenetic Protein-2) and MEK (MAP kinase/ERK kinase) inhibitor PD0325901 increases bone formation in a murine model of neurofibromatosis type I pseudarthrosis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-07-2014
DOI: 10.2106/JBJS.M.00862
Preventing osteolytic lesions and osteomyelitis in multiple myeloma
Publisher: Elsevier BV
Date: 12-2022
Cellular transitions and tissue engineering
Publisher: Mary Ann Liebert Inc
Date: 04-2013
Models of the Gut for Analyzing the Impact of Food and Drugs
Publisher: Wiley
Date: 08-10-2019
Abstract: Models of the human gastrointestinal tract (GIT) can be powerful tools for examining the biological interactions of food products and pharmaceuticals. This can be done under normal healthy conditions or using models of disease-many of which have no curative therapy. This report outlines the field of gastrointestinal modeling, with a particular focus on the intestine. Traditional in vivo animal models are compared to a range of in vitro models. In vitro systems are elaborated over time, recently culminating with microfluidic intestines-on-chips (IsOC) and 3D bioengineered models. Macroscale models are also reviewed for their important contribution in the microbiota studies. Lastly, it is discussed how in silico approaches may have utility in predicting and interpreting experimental data. The various advantages and limitations of the different systems are contrasted. It is posited that only through complementary use of these models will salient research questions be able to be addressed.
Bisphosphonate-adsorbed ceramic nanoparticles increase bone formation in an injectable carrier for bone tissue engineering
Publisher: SAGE Publications
Date: 2015
Abstract: Sucrose acetate isobutyrate (SAIB) is a sugar-based carrier. We have previously applied SAIB as a minimally invasive system for the co-delivery of recombinant human bone morphogenetic protein-2 (rhBMP-2) and found synergy when co-delivering zoledronic acid (ZA) and hydroxyapatite (HA) nanoparticles. Alternative bioceramics were investigated in a murine SAIB/rhBMP-2 injection model. Neither beta-tricalcium phosphate (TCP) nor Bioglass (BG) 45S5 had a significant effect on bone volume (BV) alone or in combination with the ZA. 14 C-labelled ZA binding assays showed particle size and ceramic composition affected binding with nano-HA micro-HA TCP BG. Micro-HA and nano-HA increased BV in a rat model of rhBMP-2/SAIB injection (+278% and +337%), and BV was further increased with ZA–adsorbed micro-HA and nano-HA (+530% and +889%). These data support the use of ZA–adsorbed nanoparticle-sized HA as an optimal additive for the SAIB/rhBMP-2 injectable system for bone tissue engineering.
Disease-modifying interactions between chronic kidney disease and osteoarthritis: a new comorbid mouse model
Publisher: BMJ
Date: 08-2023
DOI: 10.1136/RMDOPEN-2023-003109
Abstract: The prevalence of comorbid chronic kidney disease (CKD) and osteoarthritis (OA) is increasing globally. While sharing common risk factors, the mechanism and consequences of concurrent CKD-OA are unclear. The aims of the study were to develop a preclinical comorbid model, and to investigate the disease-modifying interactions. Seventy (70) male 8–10 week-old C57BL/6 mice were subjected to 5/6 nephrectomy (5/6Nx)±destabilisation of medial meniscus (DMM) or sham surgery. OA pathology and CKD were assessed 12 weeks postinduction by blinded histology scoring, micro-CT, immunohistochemistry for osteoclast and matrix metalloproteinase (MMP)-13 activity, and serum analysis of bone metabolic markers. The 5/6Nx model recapitulated characteristic features of CKD, with renal fibrosis and deranged serum alkaline phosphatase, calcium and phosphate. There was no histological evidence of cartilage pathology induced by 5/6Nx alone, however, synovial MMP-13 expression and subchondral bone osteoclastic activity were increased (p .05), with accompanying reductions (p .05) in subchondral trabecular bone, bone volume and mineral density. DMM significantly (p .05) increased tibiofemoral cartilage damage, subchondral bone sclerosis, marginal osteophytes and synovitis, in association with increased cartilage and synovial MMP-13. DMM alone induced (p .05) renal fibrosis, proteinuria and increased (p .05) 5/6Nx-induced serum urea. However, DMM in 5/6Nx-mice resulted in significantly reduced (p .05) cartilage pathology and marginal osteophyte development, in association with reduced subchondral bone volume and density, and inhibition of 5/6Nx-induced subchondral bone osteoclast activation. This study assessed a world-first preclinical comorbid CKD-OA model. Our findings demonstrate significant bidirectional disease-modifying interaction between CKD and OA.
Microalgae as a source of vitamin K1
Publisher: Elsevier BV
Date: 12-2018
Mice with myocyte deletion of vitamin D receptor have sarcopenia and impaired muscle function
Publisher: Wiley
Date: 21-06-2019
DOI: 10.1002/JCSM.12460
Abstract: It has long been recognized that vitamin D deficiency is associated with muscle weakness and falls. Vitamin D receptor (VDR) is present at very low levels in normal muscle. Whether vitamin D plays a direct role in muscle function is unknown and is a subject of hot debate. Myocyte‐specific deletion of VDR would provide a strategy to answer this question. Myocyte‐specific vitamin D receptor (mVDR) null mice were generated by crossing human skeletal actin‐Cre mice with floxed VDR mice. The effects of gene deletion on the muscle phenotype were studied in terms of body tissue composition, muscle tissue histology, and gene expression by real‐time PCR. Unlike whole‐body VDR knockout mice, mVDR mice showed a normal body size. The mVDR showed a distinct muscle phenotype featuring reduced proportional lean mass (70% vs. 78% of lean mass), reduced voluntary wheel‐running distance (22% decrease, P = 0.009), reduced average running speed, and reduced grip strength (7–16% reduction depending on age at testing). With their decreased voluntary exercise, and decreased lean mass, mVDR have increased proportional fat mass at 20% compared with 13%. Surprisingly, their muscle fibres showed slightly increased diameter, as well as the presence of angular fibres and central nuclei suggesting ongoing remodelling. There were, however, no clear changes in fibre type and there was no increase in muscle fibrosis. VDR is a transcriptional regulator, and changes in the expression of candidate genes was examined in RNA extracted from skeletal muscle. Alterations were seen in myogenic gene expression, and there was decreased expression of cell cycle genes cyclin D1 , D2 , and D3 and cyclin‐dependent kinases Cdk‐2 and Cdk‐4 . Expression of calcium handling genes sarcoplasmic/endoplasmic reticulum calcium ATPases (SERCA) Serca2b and Serca3 was decreased and Calbindin mRNA was lower in mVDR muscle. This study demonstrates that vitamin D signalling is needed for myocyte function. Despite the low level of VDR protein normally found muscle, deleting myocyte VDR had important effects on muscle size and strength. Maintenance of normal vitamin D signalling is a useful strategy to prevent loss of muscle function and size.
Sclerostin Antibody Increases Callus Size and Strength but does not Improve Fracture Union in a Challenged Open Rat Fracture Model
Publisher: Springer Science and Business Media LLC
Date: 08-04-2017
DOI: 10.1007/S00223-017-0275-2
Abstract: Open fractures remain a challenge in orthopedics. Current strategies to intervene are often inadequate, particularly in severe fractures or when treatment is delayed. Sclerostin is a negative regulator of bone growth and sclerostin-neutralizing antibodies (Scl-Ab) can increase bone mass and strength. The application of these antibodies to improve orthopedic repair has shown varied results, and may be dependent on the location and severity of the bony injury. We examined Scl-Ab treatment within an established rat osteotomy model with periosteal stripping analogous to open fracture repair. In one study, Scl-Ab was given 25 mg/kg bi-weekly, either from the time of fracture or from 3 weeks post-fracture up to an end-point of 12 weeks. A second study treated only delayed union open fractures that did not show radiographic union by week 6 post-fracture. Outcome measures included radiographic union, microCT analysis of bone volume and architecture, and histology. In the first study, Scl-Ab given from either 0 or 3 weeks significantly improved callus bone volume (+52%, p < 0.05 and +58%, p < 0.01) at 12 weeks, as well as strength (+48%, p < 0.05 and +70%, p < 0.05). Despite these improvements, union rate was not changed. In the second study treating only established delayed fractures, bony callus volume was similarly increased by Scl-Ab treatment however, this did not translate to increased biomechanical strength or union improvement. Sclerostin antibody treatment has limited effects on the healing of challenging open fractures with periosteal stripping, but shows the greatest benefits on callus size and strength with earlier intervention.
Potential application of non-thermal atmospheric plasma in reducing the activity of Pseudomonas-secreted proteases in milk
Publisher: Elsevier BV
Date: 09-2021
Bone Marrow Transplantation for Treatment of the Col1a2 +/G610C Osteogenesis Imperfecta Mouse Model
Publisher: Springer Science and Business Media LLC
Date: 08-12-2019
DOI: 10.1007/S00223-018-0504-3
Abstract: Bone marrow transplantation (BMT) of healthy donor cells has been postulated as a strategy for treating osteogenesis imperfecta (OI) and other bone fragility disorders. The effect of engraftment by tail vein injection and/or marrow ablation by 6 Gy whole body irradiation were tested in Col1a2
Effect of combined treatment with zoledronic acid and parathyroid hormone on mouse bone callus structure and composition
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.BONE.2016.08.012
Abstract: In recent years, great interest in combined treatment of parathyroid hormone (PTH) with anti-resorptive therapy has emerged. PTH has been suggested to aid bridging of atrophic fractures and improve strength in closed fracture models. Bisphosphonate treatments typically result in a larger woven bone callus that is slower to remodel. The combination of both drugs has been demonstrated to be effective for the treatment of osteoporotic bone loss in many preclinical studies. However, the effect of combined treatment on fracture repair is still largely unexplored. In this study, we aimed to compare these drugs as single-agent and in combination in a murine closed fracture model. We wanted to assess potential differences in material properties, morphometry and in the development of the lacuno-canalicular network. A total of 40 female, 11-week-old wild type mice underwent a closed fracture on the midshaft of the tibia and were assigned to four groups (n=8-10 per group). Beginning on post-operative day 8, animals received different subcutaneous injections. Group 1 received a single injection of saline solution and Group 2 of zoledronic acid (ZA). Group 3 received daily dosing of PTH. Group 4 received a dual treatment, starting with a single dose of ZA followed by daily injection of PTH. Three weeks after fracture, all animals were euthanized and tibiae were assessed using micro-computed tomography (micro-CT), high-resolution micro-CT (HR micro-CT), Raman spectroscopy, quantitative histomorphometry, and deconvolution microscopy (DV microscopy). Combined treatment showed a significant increase of 41% in bone volume fraction and a significant decrease of 61% in the standard deviation of the trabecular spacing compared to vehicle, both known to be strong predictors of callus strength. An analysis via HR micro-CT showed similar results on all groups for lacunar numerical density, whereas mean lacuna volume was found to be higher compared to vehicle in treated groups, but only PTH mono-treatment showed a significant increase compared to vehicle (+45%). Raman spectroscopy did not reveal detectable changes in material properties of the bone calluses. Sclerostin staining, tartrate resistant acid phosphatase (TRAP) staining and canalicular analysis with DV microscopy on a subset of s les did not display distinctive difference in any of the treatments. We therefore consider PTH+ZA treatment beneficial for bone healing. No clear negative effect on bone quality was detected during this study.
Modeling anabolic and antiresorptive therapies for fracture healing in a mouse model of osteogenesis imperfecta.
Publisher: Wiley
Date: 21-07-2022
DOI: 10.1002/JOR.25414
Abstract: Osteogenesis imperfecta (OI) is a genetic bone fragility disorder that features frequent fractures. Bone healing outcomes are contingent on a proper balance between bone formation and resorption, and drugs such as bone morphogenetic proteins (BMPs) and bisphosphonates (BPs) have shown to have utility in modulating fracture repair. While BPs are used for OI to increase BMD and reduce pain and fracture rates, there is little evidence for using BMPs as local agents for fracture healing (alone or with BPs). In this study, we examined wild-type and OI mice (Col1a2
In vivo local co-delivery of recombinant human bone morphogenetic protein-7 and pamidronate via poly-D, L-lactic acid
Publisher: European Cells and Materials
Date: 22-12-2010
DOI: 10.22203/ECM.V020A35
Abstract: The effects of bone anabolic agents such as bone morphogenetic proteins (BMPs) have the potential to be augmented by co-treatment with an anti-catabolic such as a bisphosphonate. We hypothesised that the effects of bisphosphonates on BMP-induced bone anabolism would be dose dependent, and we aimed to test this in a small animal model. Agents were delivered locally using a biodegradable poly-D, L-lactic-acid (PDLLA) polymer delivery system. Recombinant human BMP-7 (25 µg) was tested with a range of doses of the bisphosphonate pamidronate (0.02 mg, 0.2 mg and 2 mg local PAM 0.3 mg/kg and 3 mg/kg thrice-weekly systemic PAM) versus BMP-7 alone. Polymer pellets were surgically implanted in the hind limbs of female C57BL6/J mice (8-10 week) and ectopic bone nodules were harvested at 3 and 8 weeks post-operatively. At 3 weeks, local low dose PAM (0.02 mg) induced a 102% increase in rhBMP-7 induced bone volume (p<0.01) as measured by miroCT, and this was comparable to systemic PAM (0.3 mg/kg thrice-weekly). In contrast, local high dose PAM (2 mg) resulted in a 97% decrease in bone volume (p<0.01). Radiography and histology indicated that the polymer vehicle was still largely present at 8 weeks indicating inefficient biodegradation. This is the first study to validate the utility of local co-delivery of BMP/bisphosphonate via biodegradable polymer and supports the continued refinement of more advanced bioresorbable delivery systems for clinical applications.
NF1 is a critical regulator of muscle development and metabolism
Publisher: Oxford University Press (OUP)
Date: 24-10-2013
DOI: 10.1093/HMG/DDT515
Rapid cell culture and pre-clinical screening of a transforming growth factor-β (TGF-β) inhibitor for orthopaedics
Publisher: Springer Science and Business Media LLC
Date: 28-05-2010
Characterization of the Developing Lacunocanalicular Network During Fracture Repair
Publisher: Wiley
Date: 12-07-2021
DOI: 10.1002/JBM4.10525
Abstract: Fracture repair is a normal physiological response to bone injury. During the process of bony callus formation, a lacunocanalicular network (LCN) is formed de novo that evolves with callus remodeling. Our aim was the longitudinal assessment of the development and evolution of the LCN during fracture repair. To this end, 45 adult wild‐type C57BL/6 mice underwent closed tibial fracture surgery. Fractured and intact contralateral tibias were harvested after 2, 3, and 6 weeks of bone healing ( n = 15/group). High‐resolution micro–computed tomography (μCT) and deconvolution microscopy (DV) approaches were applied to quantify lacunar number density from the calluses and intact bone. On histological sections, Goldner's trichrome staining was used to assess lacunar occupancy, fluorescein isothiocyanate staining to visualize the canalicular network, and terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate‐biotin nick end labeling (TUNEL) staining to examine osteocyte apoptosis. Analysis of μCT scans showed progressive decreases in mean lacuna volume over time (−27% 2–3 weeks −13% 3–6 weeks). Lacunar number density increased considerably between 2 and 3 weeks (+156%). Correlation analysis was performed, showing a positive linear relationship between canalicular number density and trabecular thickness ( R 2 = 0.56, p 0.001) and an inverse relationship between mean lacuna volume and trabecular thickness ( R 2 = 0.57, p 0.001). Histology showed increases in canalicular number density over time (+22% 2–3 weeks, +51% 3–6 weeks). Lacunar occupancy in new bone of the callus was high ( %), but the old cortical bone within the fracture site appeared necrotic as it underwent resorption. In conclusion, our data shows a progressive increase in the complexity of the LCN over time during fracture healing and demonstrates that this network is initiated during the early stages of repair. Further studies are needed to address the functional importance of osteocytes in bone healing, particularly in detecting and translating the effects of micromotion in the fracture. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Use of BMPs and bisphosphonates to improve bone fracture healing
Publisher: IMR Press
Date: 2012
DOI: 10.2741/E572
Abstract: In orthopaedics, focus is often placed on increasing bone formation by an anabolic drug like the recombinant human bone morphogenetic protein (rhBMP). However, premature or excessive bone resorption, due to stress-shielding, instability or infection/inflammation can lead to poor, delayed, or absent bone union. Anti-catabolic drugs such as bisphosphonates have therefore been explored to improve bone repair. This short review discusses the current literature underlying the anabolic-catabolic paradigm for bone repair with a focus on BMP and bisphosphonate combination approaches.
Local Delivery of the Cationic Steroid Antibiotic CSA-90 Enables Osseous Union in a Rat Open Fracture Model of Staphylococcus aureus Infection
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2015
DOI: 10.2106/JBJS.N.00840
Myogenic progenitors contribute to open but not closed fracture repair.
Publisher: Springer Science and Business Media LLC
Date: 12-2011
Abstract: Bone repair is dependent on the presence of osteocompetent progenitors that are able to differentiate and generate new bone. Muscle is found in close association with orthopaedic injury, however its capacity to make a cellular contribution to bone repair remains ambiguous. We hypothesized that myogenic cells of the MyoD-lineage are able to contribute to bone repair. We employed a MyoD -Cre + :Z/AP + conditional reporter mouse in which all cells of the MyoD-lineage are permanently labeled with a human alkaline phosphatase (hAP) reporter. We tracked the contribution of MyoD-lineage cells in mouse models of tibial bone healing. In the absence of musculoskeletal trauma, MyoD-expressing cells are limited to skeletal muscle and the presence of reporter-positive cells in non-muscle tissues is negligible. In a closed tibial fracture model, there was no significant contribution of hAP + cells to the healing callus. In contrast, open tibial fractures featuring periosteal stripping and muscle fenestration had up to 50% of hAP + cells detected in the open fracture callus. At early stages of repair, many hAP + cells exhibited a chondrocyte morphology, with lesser numbers of osteoblast-like hAP + cells present at the later stages. Serial sections stained for hAP and type II and type I collagen showed that MyoD-lineage cells were surrounded by cartilaginous or bony matrix, suggestive of a functional role in the repair process. To exclude the prospect that osteoprogenitors spontaneously express MyoD during bone repair, we created a metaphyseal drill hole defect in the tibia. No hAP + staining was observed in this model suggesting that the expression of MyoD is not a normal event for endogenous osteoprogenitors. These data document for the first time that muscle cells can play a significant secondary role in bone repair and this knowledge may lead to important translational applications in orthopaedic surgery. Please see related article: 741-7015/9/136
A sugar-based phase-transitioning delivery system for bone tissue-engineering
Publisher: European Cells and Materials
Date: 22-10-2013
DOI: 10.22203/ECM.V026A15
Abstract: Bone tissue engineering approaches commonly involve the delivery of recombinant human bone morphogenetic proteins (rhBMPs). However, there are limitations associated with the currently used carriers, including the need for surgical implantation and the associated increase in infection risk. As an alternative to traditional porous collagen sponge, we have adopted a solution of the injectable sucrose acetate isobutyrate (SAIB) as a carrier for rhBMP-2. The ability to deliver rhBMP-2 and other agents by injection reduces the infection risk and lesion size whilst in surgery, with the potential to avoid open surgery altogether in some indications. The primary methodology used for this in vivo study was a C57BL6/J mouse ectopic bone formation model. Specimens were examined by x-ray, microCT, and histology at 3 weeks. SAIB was delivered non-invasively and produced up to 3-fold greater bone volume compared to collagen. To further refine and improve upon the formulation, SAIB containing rhBMP-2 was admixed with candidate compounds including ceramic microparticles, anti-resorptives, and cell signalling inhibitors and further tested in vivo. The formulation combining SAIB/rhBMP-2, the bisphosphonate zoledronic acid (ZA), and hydroxyapatite (HA) microparticles yielded a 10-fold greater bone volume than SAIB/rhBMP-2 alone. To investigate the mechanism underlying the synergy between ZA and HA, we used in vitro binding assays and in vivo fluorescent biodistribution studies to demonstrate that ceramic particles could bind and sequester the bisphosphonate. These data show the utility of SAIB as a non-invasive rhBMP delivery system as well as describing an optimised formulation for bone tissue engineering.
Long-term Outcomes of Adolescent Anorexia Nervosa on Bone
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.JADOHEALTH.2018.07.025
Abstract: Anorexia nervosa (AN) is a chronic and life-threatening eating disorder that can have a considerable negative impact on the growing skeleton. We hypothesized that the long-term impact on bone health may persist even after normalization of body weight. 41 females (mean age 21.2 ± 2.9 years) with a history of adolescent-onset AN attended a follow-up bone health assessment at 5 years (T5, n = 28) or 10 years (T10, n = 13) after their first AN-related hospital admission. Assessment included dual-energy x-ray absorptiometry measurements of the total body, lumbar spine, and proximal femur, peripheral quantitative computed tomography at the radius and tibia, anthropometric measurements, serum biochemistry, fracture history, and a patient questionnaire. A recovery in body weight and BMI was seen for both the T5 and T10 cohorts (BMI at intake 16.6, BMI at T5-T10 21.2-21.3). Dual-energy x-ray absorptiometry body composition indicated a recovery of fat mass and lean tissue mass. Total BMD was unaffected, but reductions were seen at the femoral neck and arms. Peripheral quantitative computed tomography showed reduced trabecular and cortical bone in the radius, and cortical thinning in the tibia. AN patients showed a statistically significant reduction in measures of radiographic bone health at follow up, although not to a degree that necessitated clinical intervention. Serum insulin-like growth factor 1 was also positively correlated with total BMD and BMC measures. While fracture risk was not increased, a subset of participants (8%) showed multiple (>4) fractures. A longitudinal study of adolescent AN showed persisting negative effects on bone health.
Diagnosis of Recurrent Fracture in a Pediatric Cohort
Publisher: Springer Science and Business Media LLC
Date: 25-06-2018
DOI: 10.1007/S00223-018-0449-6
Abstract: Significant fracture history in children is defined as having at least one vertebral fracture, at least 2 fractures by age 10, or at least 3 fractures by age 19. Between September 2011 and December 2014, clinical data were collected on children with a significant fracture history that attended a major Australian children's hospital. Fifty-six patients were identified as having 305 fractures in total, including 44 vertebral fractures. 18% of patients (10/56) were diagnosed with osteogenesis imperfecta (OI) by a bone health expert, molecular testing or both, and they sustained 23% of all fractures (71/305). Analysis of serum bone biochemistry showed all median values to be within a normal range and no clinically significant differences between patients with and without OI. The DXA and pQCT derived bone mineral density (BMD) and bone mineral content (BMC) Z scores were reduced overall. DXA derived total body and lumbar spine areal BMD-for-age and BMC-for-age Z scores were significantly lower in children who had vertebral fractures or who were later diagnosed with OI. Similarly, pQCT performed on radii and tibiae showed Z scores significantly less than zero. pQCT-derived limb muscle cross sectional area Z scores were significantly lower in the OI subgroup. In conclusion, this study describes the bone phenotype of children referred to a tertiary hospital clinic for recurrent fractures and highlights a subset of children with previously undiagnosed OI, but a larger cohort without classic OI. Thus it can be clinically challenging to differentiate between children with OI type 1 (mild phenotype) and non-OI children without bone densitometry and genetic testing. We conclude that recurrent fractures in children should prompt a comprehensive bone and systemic health assessment to eliminate an underlying pathology.
Lineage tracking of mesenchymal and endothelial progenitors in BMP-induced bone formation
Publisher: Elsevier BV
Date: 12-2015
Recent insights into bone development, homeostasis, and repair in type 1 neurofibromatosis (NF1)
Publisher: Elsevier BV
Date: 04-2008
DOI: 10.1016/J.BONE.2007.11.006
Abstract: Neurofibromatosis type 1 (NF1) is one of the most common single gene syndromes and is typified by a range of characteristic but variably penetrant manifestations. The orthopaedic manifestations of congenital pseudarthrosis of the tibia (CPT) and scoliosis, along with other skeletal defects including sphenoid wing dysplasia, rib penciling, and gracile bones have been classically associated with NF1. Added to this, several recent studies have reported a high prevalence of osteoporosis or osteopenia in NF1 cohorts. Clues to the underlying molecular and cellular deficiencies that cause these bony defects can be gleaned from genetically modified mouse models of Nf1 gene deficiency. These studies suggest that a variety of different cell lineages may be adversely affected by Nf1 haploinsufficiency or by double inactivation of the Nf1 gene. Osteoblasts, osteoclasts, chondrocytes, fibroblasts, and vascular endothelial cells all express the Nf1 gene product, neurofibromin, and may be functionally compromised when levels are decreased or absent. This paper reviews the current literature on NF1 bone development, homeostatic regulation, and repair, and highlights some emerging themes that may have relevance for managing orthopaedic disorders that can arise in in iduals with NF1.
Modeling bone morphogenetic protein and bisphosphonate combination therapy in wild-type and Nf1 haploinsufficient mice
Publisher: Wiley
Date: 04-09-2007
DOI: 10.1002/JOR.20481
Abstract: Recombinant bone morphogenetic proteins (BMPs) show promise in treating the orthopedic complications associated with neurofibromatosis type 1 (NF1), such as congenital pseudarthrosis of the tibia. Minimal scientific information regarding the effects of BMP in the context of NF1 is available. As abnormalities in both bone formation and resorption have been documented in Nf1-deficient mice, we hypothesized that inadequate BMP-induced bone formation could be augmented by cotreatment with the bisphosphonate zoledronic acid (ZA). First, primary osteoblasts isolated from wild type (Nf1(+/+)) and Nf1-deficient (Nf1(+/-)) mice were cultured in the presence and absence of BMP-2. While Nf1(+/-) cells exhibited less osteogenic potential than Nf1(+/+) cells, alkaline phosphatase expression and matrix mineralization for both genotypes were enhanced by BMP-2 treatment. To model this response in vivo, 20 microg BMP-2 was implanted intramuscularly into the quadriceps of mice to induce heterotopic bone. Radiographs revealed significantly less net bone formation in Nf1(+/-) mice compared to Nf1(+/+) controls. To test the effect of an antiresorptive agent, mice were cotreated twice weekly from postoperative day 3 with 0.02 mg/kg ZA or with saline. ZA treatment led to a synergistic increase in the amount of heterotopic bone in both Nf1(+/+) and Nf1(+/-) mice compared with saline controls, as measured by DEXA and histomorphometry. Thus, the anabolic deficiency noted in Nf1(+/-) mice is amenable to stimulation by BMP-2, but mineralized tissue formation remains below that of Nf1(+/+) controls. Bisphosphonate combination therapy is superior to BMP therapy alone in terms of net bone production in vivo in both wild-type and Nf1-deficient mice.
Murine models of orthopedic infection featuring Staphylococcus aureus biofilm
Publisher: Copernicus GmbH
Date: 07-03-2023
Abstract: Abstract. Introduction: Osteomyelitis remains a major clinical challenge. Many published rodent fracture infection models are costly compared with murine models for rapid screening and proof-of-concept studies. We aimed to develop a dependable and cost-effective murine bone infection model that mimics bacterial bone infections associated with biofilm and metal implants. Methods: Tibial drilled hole (TDH) and needle insertion surgery (NIS) infection models were compared in C57BL/6 mice (female, N=150). Metal pins were inserted selectively into the medullary canal adjacent to the defect sites on the metaphysis. Free Staphylococcus aureus (ATCC 12600) or biofilm suspension (ATCC 25923) was locally inoculated. Animals were monitored for physiological or radiographic evidence of infection without prophylactic antibiotics for up to 14 d. At the end point, bone swabs, soft-tissue biopsies, and metal pins were taken for cultures. X-ray and micro-CT scans were performed along with histology analysis. Results: TDH and NIS both achieved a 100 % infection rate in tibiae when a metal implant was present with injection of free bacteria. In the absence of an implant, inoculation with a bacterial biofilm still induced a 40 %–50 % infection rate. In contrast, freely suspended bacteria and no implant consistently showed lower or negligible infection rates. Micro-CT analysis confirmed that biofilm infection caused local bone loss even without a metal implant as a nidus. Although a metal surface permissive for biofilm formation is impermeable to create progressive bone infections in animal models, the metal implant can be dismissed if a bacterial biofilm is used. Conclusion: These models have a high potential utility for modeling surgery-related osteomyelitis, with NIS being simpler to perform than TDH.
Characterization of the bone phenotype and fracture repair in osteopetrotic Incisors absent rats
Publisher: Wiley
Date: 03-12-2010
DOI: 10.1002/JOR.21293
Abstract: Osteopetrotic patients possess a genetic condition that leads to a deficiency in osteoclast number or function. Patients have a high bone density and suffer from an increased risk of fracture. The lack of normal osteoclast activity has the potential to impede repair by complicating orthopedic fixation and/or by affecting the biology of fracture healing. The naturally occurring incisors absent (ia/ia) rat was adopted as a rodent model of congenital osteopetrosis. A detailed phenotypic analysis of the ia/ia rat indicated that some functional recovery occurred between 7 and 9 weeks. Consequently a fracture repair study was undertaken using 5-week-old rats. Closed femoral fractures were generated in ia/ia rats and control ia/+ and +/+ rats using an Einhorn apparatus. Fracture healing was examined radiologically and histologically at 1-3 weeks. No difference was seen in bridging between ia/ia and control rats at any time point. The ia/ia rats showed no delay in cartilage removal but showed a significant delay in hard callus remodeling. This is consistent with an essential role for osteoclasts in only the latter stages of endochondral bone repair. This delay in hard callus remodeling was offset by an increase in moment of inertia.
Nanoscale Chemical Interaction Enhances the Physical Properties of Bioglass Composites
Publisher: American Chemical Society (ACS)
Date: 16-12-2013
DOI: 10.1021/NN402157N
Abstract: Bioglasses are favorable biomaterials for bone tissue engineering however, their applications are limited due to their brittleness. In addition, the early failure in the interface is a common problem of composites of bioglass and a polymer with high mechanical strength. This effect is due to the phase separation, nonhomogeneous mixture, nonuniform mechanical strength, and different degradation properties of two compounds. To address these issues, in this study a nanoscale interaction between poly(methyl methacrylate) (PMMA) and bioactive glass was formed via silane coupling agent (3-trimethoxysilyl)propyl methacrylate (MPMA). A monolith was produced at optimum composition from this hybrid by the sol-gel method at 50 °C with a rapid gelation time (<50 min) that possessed superior physicochemical properties compared to pure bioglass and physical mixture. For instance, the Young's modulus of bioglass was decreased 40-fold and the dissolution rate of silica was retarded 1.5-fold by integration of PMMA. Prolonged dissolution of silica fosters bone integration due to the continuous dissolution of bioactive silica. The primary osteoblast cells were well anchored and cell migration was observed on the surface of the hybrid. The in vivo studies in mice demonstrated that the integrity of the hybrids was maintained in subcutaneous implantation. They induced mainly a mononuclear phagocytic tissue reaction with a low level of inflammation, while bioglass provoked a tissue reaction with TRAP-positive multinucleated giant cells. These results demonstrated that the presence of a nanoscale interaction between bioglass and PMMA affects the properties of bioglass and broadens its potential applications for bone replacement.
Effect of rapamycin on bone mass and strength in the α2(I)‐G610C mouse model of osteogenesis imperfecta
Publisher: Wiley
Date: 30-12-2018
DOI: 10.1111/JCMM.14072
Cell-scaffold interactions in the bone tissue engineering triad
Publisher: European Cells and Materials
Date: 20-09-2013
DOI: 10.22203/ECM.V026A09
Abstract: Bone tissue engineering has emerged as one of the leading fields in tissue engineering and regenerative medicine. The success of bone tissue engineering relies on understanding the interplay between progenitor cells, regulatory signals, and the biomaterials/scaffolds used to deliver them--otherwise known as the tissue engineering triad. This review will discuss the roles of these fundamental components with a specific focus on the interaction between cell behaviour and scaffold structural properties. In terms of scaffold architecture, recent work has shown that pore size can affect both cell attachment and cellular invasion. Moreover, different materials can exert different biomechanical forces, which can profoundly affect cellular differentiation and migration in a cell type specific manner. Understanding these interactions will be critical for enhancing the progress of bone tissue engineering towards clinical applications.
Increased anabolic bone response in Dkk1 KO mice following tibial compressive loading
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.BONE.2019.115054
Abstract: A viable Dkk1 knockout (KO) mouse strain in which embryonic lethality is rescued by developmental Wnt3 heterozygosity (Dkk1
Update from the 2013 international neurofibromatosis conference
Publisher: Wiley
Date: 24-09-2014
DOI: 10.1002/AJMG.A.36754
Animal models of scoliosis
Publisher: Wiley
Date: 23-03-2015
DOI: 10.1002/JOR.22797
Abstract: Multiple techniques designed to induce scoliotic deformity have been applied across many animal species. We have undertaken a review of the literature regarding experimental models of scoliosis in animals to discuss their utility in comprehending disease aetiology and treatment. Models of scoliosis in animals can be broadly ided into quadrupedal and bipedal experiments. Quadrupedal models, in the absence of axial gravitation force, depend upon development of a mechanical asymmetry along the spine to initiate a scoliotic deformity. Bipedal models more accurately mimic human posture and consequently are subject to similar forces due to gravity, which have been long appreciated to be a contributing factor to the development of scoliosis. Many effective models of scoliosis in smaller animals have not been successfully translated to primates and humans. Though these models may not clarify the aetiology of human scoliosis, by providing a reliable and reproducible deformity in the spine they are a useful means with which to test interventions designed to correct and prevent deformity.
A collagen-hydroxyapatite scaffold allows for binding and co-delivery of recombinant bone morphogenetic proteins and bisphosphonates
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.ACTBIO.2014.01.016
Abstract: An emerging paradigm in orthopedics is that a bone-healing outcome is the product of the anabolic (bone-forming) and catabolic (bone-resorbing) outcomes. Recently, surgical and tissue engineering strategies have emerged that combine recombinant human bone morphogenetic proteins (rhBMPs) and bisphosphonates (BPs) in order to maximize anabolism and minimize catabolism. Collagen-based scaffolds that are the current surgical standard can bind rhBMPs, but not BPs. We hypothesized that a biomimetic collagen-hydroxyapatite (CHA) scaffold would bind both agents and produce superior in vivo outcomes. Consistent with this concept, in vitro elution studies utilizing rhBMP-2 ELISA assays and scintillation counting of (14)C-radiolabeled zoledronic acid (ZA) confirmed delayed release of both agents from the CHA scaffold. Next, scaffolds were tested for their capacity to form ectopic bone after surgical implantation into the rat hind limb. Using CHA, a significant 6-fold increase in bone volume was seen in rhBMP-2/ZA groups compared to rhBMP-2 alone, confirming the ability of ZA to enhance rhBMP-2 bone formation. CHA scaffolds were found to be capable of generating mineralized tissue in the absence of rhBMP-2. This study has implications for future clinical treatments of critical bone defects. It demonstrates the relative advantages of co-delivering anabolic and anti-catabolic agents using a multicomponent scaffold system.
Osteoclasts but not osteoblasts are affected by a calcified surface treated with zoledronic acid in vitro
Publisher: Elsevier BV
Date: 12-2005
DOI: 10.1016/J.BBRC.2005.09.198
Abstract: Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption. Recent interest has centered on the effects of bisphosphonates on osteoblasts. Chronic dosing of osteoblasts with solubilized bisphosphonates has been reported to enhance osteogenesis and mineralization in vitro. However, this methodology poorly reflects the in vivo situation, where free bisphosphonate becomes rapidly bound to mineralized bone surfaces. To establish a more clinically relevant cell culture model, we cultured bone cells on calcium phosphate coated quartz discs pre-treated with the potent nitrogen-containing bisphosphonate, zoledronic acid (ZA). Binding studies utilizing [(14)C]-labeled ZA confirmed that the bisphosphonate bound in a concentration-dependent manner over the 1-50microM dose range. When grown on ZA-treated discs, the viability of bone-marrow derived osteoclasts was greatly reduced, while the viability and mineralization of the osteoblastic MC3T3-E1 cell line were largely unaffected. This suggests that only bone resorbing cells are affected by bound bisphosphonate. However, this system does not account for transient exposure to unbound bisphosphonate in the hours following a clinical dosing. To model this event, we transiently treated osteoblasts with ZA in the absence of a calcified surface. Osteoblasts proved highly resistant to all transitory treatment regimes, even when utilizing ZA concentrations that prevented mineralization and/or induced cell death when dosed chronically. This study represents a pharmacologically more relevant approach to modeling bisphosphonate treatment on cultured bone cells and implies that bisphosphonate therapies may not directly affect osteoblasts at bone surfaces.
BMP‐2 delivered via sucrose acetate isobutyrate (SAIB) improves bone repair in a rat open fracture model
Publisher: Wiley
Date: 08-01-2016
DOI: 10.1002/JOR.23131
Abstract: Human bone morphogenetic proteins (BMPs) are an alternative to bone graft for the treatment of high-energy open fractures. The standard delivery system for BMP-2 is a porous collagen sponge, but we have previously found that the biocompatible, high viscosity carrier, Sucrose acetate isobutyrate (SAIB) is an effective and potentially less invasive alternative. The efficacy of SAIB as a BMP-2 delivery system was examined in an open fracture model featuring a femoral osteotomy with periosteal stripping in 9-week-old male Sprague Dawley rats. SAIB containing BMP-2 (SAIB/BMP-2) was delivered into the fracture site during surgery and an additional group was further co-treated with zoledronic acid and hydroxyapatite nanoparticles (SAIB/BMP-2/HA/ZA). These were compared to untreated fractures and SAIB carrier alone (negative controls), and BMP-2 loaded collagen sponge (positive control). The rate of radiographic union and the biomechanical properties of the healed fractures were compared after 6-week. Untreated and SAIB-treated fractures showed poor repair, with 53% and 64%, respectively, not bridged at 6 week. In contrast, collagen/BMP-2, SAIB/BMP-2, and SAIB/BMP-2/HA/ZA showed significantly increased union (100%, 100%, and 94%, respectively, p < 0.05). Four-point bend testing revealed that collagen/BMP-2 and SAIB/BMP-2/HA/ZA restored the strength of fractured femora to that of intact femora by 6 week, whereas untreated and SAIB remained less than intact controls by 60% and 67%, respectively (p < 0.05). Overall, the SAIB/BMP-2/HA/ZA formulation was comparable to BMP-2 infused collagen sponge in terms of promoting open fractures repair, but with the additional potential for less invasive delivery. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1168-1176, 2016.
Bone remodeling during fracture repair: The cellular picture
Publisher: Elsevier BV
Date: 10-2008
DOI: 10.1016/J.SEMCDB.2008.07.004
Abstract: Fracture healing is a complex event that involves the coordination of a variety of different processes. Repair is typically characterized by four overlapping stages: the initial inflammatory response, soft callus formation, hard callus formation, initial bony union and bone remodeling. However, repair can also be seen to represent a juxtaposition of two distinct forces: anabolism or tissue formation, and catabolism or remodeling. These anabolic/catabolic concepts are useful for understanding bone repair without giving the false impression of temporally distinct stages that operate independently. They are also relevant when considering intervention. In normal bone development, bone remodeling conventionally refers to the removal of calcified bone tissue by osteoclasts. However, in the context of bone repair there are two phases of tissue catabolism: the removal of the initial cartilaginous soft callus, followed by the eventual remodeling of the bony hard callus. In this review, we have attempted to examine catabolism/remodeling in fractures in a systematic fashion. The first section briefly summarizes the traditional four-stage view of fracture repair in a physiological manner. The second section highlights some of the limitations of using a temporal rather than process-driven model and summarizes the anabolic/catabolic paradigm of fracture repair. The third section examines the cellular participants in soft callus remodeling and in particular the role of the osteoclast in endochondral ossification. Finally, the fourth section examines the effects of delaying osteoclast-dependent hard callus remodeling and also poses questions regarding the crosstalk between anabolism and catabolism in the latter stages of fracture repair.
FGF23, Hypophosphatemia, and Emerging Treatments
Publisher: Wiley
Date: 13-05-2019
DOI: 10.1002/JBM4.10190
Modulation of spine fusion with BMP-2, MEK inhibitor (PD0325901), and zoledronic acid in a murine model of NF1 double inactivation
Publisher: Elsevier BV
Date: 07-2020
Bioactive poly(methyl methacrylate) for bone fixation
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5RA08824K
Abstract: An efficient and specifically formulated superior hybrid of poly(methyl methacrylate) and bioactive glass as a bone fixation biomaterial.
A hybrid process for increasing the shelf life of elderberry juice
Publisher: Elsevier BV
Date: 10-2018
Lipid storage myopathies: Current treatments and future directions
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.PLIPRES.2018.08.001
Abstract: Lipid storage myopathies (LSMs) are a heterogeneous group of genetic disorders that present with abnormal lipid storage in multiple body organs, typically muscle. Patients can clinically present with cardiomyopathy, skeletal muscle weakness, myalgia, and extreme fatigue. An early diagnosis is crucial, as some LSMs can be managed by simple nutraceutical supplementation. For ex le, high dosage l-carnitine is an effective intervention for patients with Primary Carnitine Deficiency (PCD). This review discusses the clinical features and management practices of PCD as well as Neutral Lipid Storage Disease (NLSD) and Multiple Acyl-CoA Dehydrogenase Deficiency (MADD). We provide a detailed summary of current clinical management strategies, highlighting issues of high-risk contraindicated treatments with case study ex les not previously reviewed. Additionally, we outline current preclinical studies providing disease mechanistic insight. Lastly, we propose that a number of other conditions involving lipid metabolic dysfunction that are not classified as LSMs may share common features. These include Neurofibromatosis Type 1 (NF1) and autoimmune myopathies, including Polymyositis (PM), Dermatomyositis (DM), and Inclusion Body Myositis (IBM).
Homozygous Dkk1 Knockout Mice Exhibit High Bone Mass Phenotype Due to Increased Bone Formation
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
Formation of porous biodegradable scaffolds based on poly(propylene carbonate) using gas foaming technology.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.MSEC.2018.11.088
Abstract: Polyester-based scaffolds have been employed in tissue engineering due to their biocompatibility, biodegradability, microstructure, and affordability. However, the acidic degradation byproducts of most common polyesters have the potential to cause inflammation and/or necrosis. In this study, we introduce a porous scaffold with benign degradation byproducts fabricated by gas-foaming based on poly(propylene carbonate) (PPC) blended with starch and bioglass particles. The pore sizes ranged from 100 to 500 μm. Manufacturing parameters were tuned from sub-critical to super-critical conditions to optimize porosity, pore size, pore interconnectivity, and mechanical properties. The biological behavior of the constructs was evaluated by in vitro toxicity and proliferation assays and in vivo subcutaneous biocompatibility. Tissue integration was observed in a joint implantation model, supporting the further development of the scaffold for tissue engineering applications.
CSA-90 Promotes Bone Formation and Mitigates Methicillin-resistant Staphylococcus aureus Infection in a Rat Open Fracture Model
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 26-04-2018
DOI: 10.1097/01.BLO.0000533624.79802.E1
Abstract: Infection of open fractures remains a significant cause of morbidity and mortality to patients worldwide. Early administration of prophylactic antibiotics is known to improve outcomes however, increasing concern regarding antimicrobial resistance makes finding new compounds for use in such cases a pressing area for further research. CSA-90, a synthetic peptidomimetic compound, has previously demonstrated promising antimicrobial action against Staphylococcus aureus in rat open fractures. However, its efficacy against antibiotic-resistant microorganisms, its potential as a therapeutic agent in addition to its prophylactic effects, and its proosteogenic properties all require further investigation. (1) Does prophylactic treatment with CSA-90 reduce infection rates in a rat open fracture model inoculated with S aureus , methicillin-resistant S aureus (MRSA), and methicillin-resistant Staphylococcus epidermidis (MRSE) as measured by survival, radiographic union, and deep tissue swab cultures? (2) Does CSA-90 reduce infection rates when administered later in the management of an open fracture as measured by survival, radiographic union, and deep tissue swab cultures? (3) Does CSA-90 demonstrate a synergistic proosteogenic effect with bone morphogenetic protein 2 (BMP-2) in a noninfected rat ectopic bone formation assay as assessed by micro-CT bone volume measurement? (4) Can CSA-90 elute and retain its antimicrobial efficacy in vitro when delivered using clinically relevant agents measured using a Kirby-Bauer disc diffusion assay? All in vivo studies were approved by the local animal ethics committee. In the open fracture studies, 12-week-old male Wistar rats underwent open midshaft femoral fractures stabilized with a 1.1-mm Kirschner wire and 10 µg BMP-2 ± 500 µg CSA-90 was applied to the fracture site using a collagen sponge along with 1 x 10 4 colony-forming units of bacteria ( S aureus /MRSA/MRSE n = 10 per group). In the delayed treatment study, débridement and treatment with 500 µg CSA-90 were performed at Day 1 and Day 5 after injury and bacterial insult ( S aureus ). All animals were reviewed daily for signs of local infection and/or sepsis. An independent, blinded veterinarian reviewed twice-weekly radiographs, and rats showing osteolysis and/or declining overall health were culled at his instruction. The primary outcome of both fracture studies was fracture infection, incorporating survival, radiographic union, and deep tissue swab cultures. For the ectopic bone formation assay, 0 to 10 µg BMP-2 and 0 to 500 µg CSA-90 were delivered on a collagen sponge into bilateral quadriceps muscle pouches of 8-week-old rats (n = 10 per group). Micro-CT quantification of bone volume and descriptive histologic analysis were performed for all in vivo studies. Modified Kirby-Bauer disc diffusion assays were used to quantify antimicrobial activity in vitro using four different delivery methods, including bone cement. Infection was observed in none of the MRSA inoculated open fractures treated with CSA-90 with 10 of 10 deep tissue swab cultures negative at the time of cull. Median survival was 43 days (range, 11-43 days) in the treated group versus 11 days (range, 8-11 days) in the untreated MRSA inoculated group (p 0.001). However, delayed débridement and treatment of open fractures with CSA-90 at either Day 1 or Day 5 did not prevent infection, resulting in early culls by Day 21 with positive swab cultures (10 of 10 for each time point). Maximal ectopic bone formation was achieved with 500 μg CSA-90 and 10 μg BMP-2 (mean volume, 9.58 mm 3 SD, 7.83), creating larger bone nodules than formed with 250 μg CSA-90 and 10 μg BMP-2 (mean volume, 1.7 mm 3 SD, 1.07 p 0.001). Disc diffusion assays showed that CSA-90 could successfully elute from four potential delivery agents including calcium sulphate (mean zone of inhibition, 11.35 mm SD, 0.957) and bone cement (mean, 4.67 mm SD, 0.516). CSA-90 shows antimicrobial action against antibiotic-resistant Staphylococcal strains in vitro and in an in vivo model of open fracture infection. The antimicrobial properties of CSA-90 combined with further evidence of its proosteogenic potential make it a promising compound to develop further for orthopaedic applications.
Targeted postnatal knockout of Sclerostin using a bone-targeted adeno-associated viral vector increases bone anabolism and decreases canalicular density
Publisher: Elsevier BV
Date: 02-2023
Homeodomain factor Nkx2-5 in heart development and disease
Publisher: Cold Spring Harbor Laboratory
Date: 2002
Evaluating modified diets and dietary supplement therapies for reducing muscle lipid accumulation and improving muscle function in neurofibromatosis type 1 (NF1)
Publisher: Public Library of Science (PLoS)
Date: 10-08-2020
Combination sclerostin antibody and zoledronic acid treatment outperforms either treatment alone in a mouse model of osteogenesis imperfecta
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.BONE.2017.04.016
Abstract: In this study, we examined the therapeutic potential of anti-Sclerostin Antibody (Scl-Ab) and bisphosphonate treatments for the bone fragility disorder Osteogenesis Imperfecta (OI). Mice with the Amish OI mutation (Col1a2 G610C mice) and control wild type littermates (WT) were treated from week 5 to week 9 of life with (1) saline (control), (2) zoledronic acid given 0.025mg/kg s.c. weekly (ZA), (3) Scl-Ab given 50mg/kg IV weekly (Scl-Ab), or (4) a combination of both (Scl-Ab/ZA). Functional outcomes were prioritized and included bone mineral density (BMD), bone microarchitecture, long bone bending strength, and vertebral compression strength. By dual-energy absorptiometry, Scl-Ab treatment alone had no effect on tibial BMD, while ZA and Scl-Ab/ZA significantly enhanced BMD by week 4 (+16% and +27% respectively, P<0.05). Scl-Ab/ZA treatment also led to increases in cortical thickness and tissue mineral density, and restored the tibial 4-point bending strength to that of control WT mice. In the spine, all treatments increased compression strength over controls, but only the combined group reached the strength of WT controls. Scl-Ab showed greater anabolic effects in the trabecular bone than in cortical bone. In summary, the Scl-Ab/ZA intervention was superior to either treatment alone in this OI mouse model, however further studies are required to establish its efficacy in other preclinical and clinical scenarios.
Activated protein C (APC) can increase bone anabolism via a protease-activated receptor (PAR)1/2 dependent mechanism
Publisher: Wiley
Date: 15-09-2014
DOI: 10.1002/JOR.22726
Abstract: Activated Protein C (APC) is an anticoagulant with strong cytoprotective properties that has been shown to promote wound healing. In this study APC was investigated for its potential orthopedic application using a Bone Morphogenetic Protein 2 (rhBMP-2) induced ectopic bone formation model. Local co-administration of 10 µg rhBMP-2 with 10 µg or 25 µg APC increased bone volume at 3 weeks by 32% (N.S.) and 74% (p<0.01) compared to rhBMP-2 alone. This was associated with a significant increase in CD31+ and TRAP+ cells in tissue sections of ectopic bone, consistent with enhanced vascularity and bone turnover. The actions of APC are largely mediated by its receptors endothelial protein C receptor (EPCR) and protease-activated receptors (PARs). Cultured pre-osteoblasts and bone nodule tissue sections were shown to express PAR1/2 and EPCR. When pre-osteoblasts were treated with APC, cell viability and phosphorylation of ERK1/2, Akt, and p38 were increased. Inhibition with PAR1 and sometimes PAR2 antagonists, but not with EPCR blocking antibodies, ameliorated the effects of APC on cell viability and kinase phosphorylation. These data indicate that APC can affect osteoblast viability and signaling, and may have in vivo applications with rhBMP-2 for bone repair.
Preliminary experience with the combined use of recombinant bone morphogenetic protein and bisphosphonates in the treatment of congenital pseudarthrosis of the tibia
Publisher: SAGE Publications
Date: 12-2010
DOI: 10.1007/S11832-010-0293-3
Abstract: Congenital pseudarthrosis of the tibia (CPT) is a rare but serious disorder in children. No single approach has clearly emerged as superior in terms of operative procedure, fixation, optimal time for surgery or adjunctive pharmaceutical intervention. CPT is frequently associated with neurofibromatosis type 1 (NF1), a condition featuring deficient bone anabolism and excessive catabolism. We have therefore combined the use of bone morphogenetic proteins (BMP) with bisphosphonates (BP) as an adjunct to surgical intervention. Between 2002 and 2008 we administered BMP-7 (OP-1) at the time of surgery followed by BP (pamidronate or zoledronic acid) in eight Crawford type IV CPT cases in seven patients (six with a confirmed diagnosis of NF1) with a median age of 7 years (range 2 years 11 months to 12 years) at surgery. In six of eight cases, this approach led to primary healing after a mean of 5.5 months (range 4–7 months). One of these cases represented 17 months after primary healing of a proximal CPT with a new further distal fracture that required multiple operations to finally unite at 19 months. The two remaining cases ultimately reached union after multiple operations at 14 and 30 months, respectively, but required recent treatment for refractures. Based on these clinical data (primary healing in 6/8 cases) and prior pre-clinical findings, we propose that BP therapy may be helpful in preserving the BMP-induced bone formation by inhibiting the osteoclastic bone loss. Key factors to achieve union in CPT include sufficient fixation, meticulous resection of the dysplastic tissue and the establishment of a net anabolic environment for bone healing. Whether our biological concept of balancing the anabolic and catabolic responses with BMP and BP improves healing rates in the complex treatment of NF1 CPT remains uncertain and warrants larger prospective multicentre trials.
Printed, Flexible pH Sensor Hydrogels for Wet Environments
Publisher: Wiley
Date: 10-09-2018
Fabrication of a Biodegradable Implant with Tunable Characteristics for Bone Implant Applications
Publisher: American Chemical Society (ACS)
Date: 23-05-2017
DOI: 10.1021/ACS.BIOMAC.7B00078
Abstract: Biodegradable polymers are appealing material for the manufacturing of surgical implants as such implants break down in vivo, negating the need for a subsequent operation for removal. Many biocompatible polymers produce acidic breakdown products that can lead to localized inflammation and osteolysis. This study assesses the feasibility of fabricating implants out of poly(propylene carbonate) (PPC)-starch that degrades into CO
Highly substituted calcium silicates 3D printed with complex architectures to produce stiff, strong and bioactive scaffolds for bone regeneration
Publisher: Elsevier BV
Date: 12-2021
Personalized Baghdadite scaffolds: stereolithography, mechanics and in vivo testing
Publisher: Elsevier BV
Date: 09-2021
Posterolateral inter-transverse lumbar fusion in a mouse model
Publisher: Springer Science and Business Media LLC
Date: 23-01-2013
Abstract: Spinal fusion is a common orthopaedic procedure that has been previously modeled using canine, lapine, and rodent subjects. Despite the increasing availability of genetically modified mouse strains, murine models have only been infrequently described. To present an efficient and minimally traumatic procedure for achieving spinal fusion in a mouse model and determine the optimal rhBMP-2 dose to achieve sufficient fusion mass. MicroCT reconstructions of the unfused mouse spine and human spine were compared to design a surgical approach. In phase 1, posterolateral lumbar spine fusion in the mouse was evaluated using 18 animals allocated to three experimental groups. Group 1 received decortication only (n = 3), Group 2 received 10 μg rhBMP-2 in a collagen sponge bilaterally (n = 6), and Group 3 received 10 μg rhBMP-2 + decortication (n = 9). The surgical technique was assessed for intra-operative safety, efficacy, access and reproducibility. Spines were harvested for analysis at 3 weeks (Groups 1, 2) and 1, 2, and 3 weeks (Group 3). In phase 2, a dose response study was carried out in an additional 18 animals with C57BL6 mice receiving sponges containing 0, 0.5, 1, 2.5, 5 μg of rhBMP-2 per sponge bilaterally. The operative procedure via midline access was rapid and reproducible, and fusion of the murine articular processes was found to be analogous to the human procedure. Unlike reports from other species, decortication alone (Group 1) yielded no new bone formation. Addition of rhBMP-2 (Groups 2 and 3) yielded a significant bone mass that bridged the L4-L6 vertebrae. The subsequent dose response experiment revealed that 0.5 μg rhBMP-2 per sponge was sufficient to create a fusion mass. We describe a new approach for mouse lumbar spine fusion that is safe, efficient, and highly reproducible. The technique we employed is analogous to the human midline procedure and may be highly suitable for genetically modified mouse models.
Recovery of high-value compounds from food by-products
Publisher: Elsevier
Date: 2021
alpha-Actinin-3 deficiency is associated with reduced bone mass in human and mouse
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.BONE.2011.07.009
Abstract: Bone mineral density (BMD) is a complex trait that is the single best predictor of the risk of osteoporotic fractures. Candidate gene and genome-wide association studies have identified genetic variations in approximately 30 genetic loci associated with BMD variation in humans. α-Actinin-3 (ACTN3) is highly expressed in fast skeletal muscle fibres. There is a common null-polymorphism R577X in human ACTN3 that results in complete deficiency of the α-actinin-3 protein in approximately 20% of Eurasians. Absence of α-actinin-3 does not cause any disease phenotypes in muscle because of compensation by α-actinin-2. However, α-actinin-3 deficiency has been shown to be detrimental to athletic sprint ower performance. In this report we reveal additional functions for α-actinin-3 in bone. α-Actinin-3 but not α-actinin-2 is expressed in osteoblasts. The Actn3(-/-) mouse displays significantly reduced bone mass, with reduced cortical bone volume (-14%) and trabecular number (-61%) seen by microCT. Dynamic histomorphometry indicated this was due to a reduction in bone formation. In a cohort of postmenopausal Australian women, ACTN3 577XX genotype was associated with lower BMD in an additive genetic model, with the R577X genotype contributing 1.1% of the variance in BMD. Microarray analysis of cultured osteoprogenitors from Actn3(-/-) mice showed alterations in expression of several genes regulating bone mass and osteoblast/osteoclast activity, including Enpp1, Opg and Wnt7b. Our studies suggest that ACTN3 likely contributes to the regulation of bone mass through alterations in bone turnover. Given the high frequency of R577X in the general population, the potential role of ACTN3 R577X as a factor influencing variations in BMD in elderly humans warrants further study.
Interplay of Nkx3. 2, Sox9 and Pax3 regulates chondrogenic differentiation of muscle progenitor cells
Publisher: Public Library of Science (PLoS)
Date: 02-07-2012
Mechanical Load Increases in Bone Formation via a Sclerostin‐Independent Pathway
Publisher: Wiley
Date: 20-10-2014
DOI: 10.1002/JBMR.2278
Virtual screening and in vitro validation of natural compound inhibitors against SARS-CoV-2 spike protein
Publisher: Elsevier BV
Date: 02-2022
Limitations of the Pax7-creERT2 transgene for driving deletion of Nf1 in adult mouse muscle
Publisher: UPV/EHU Press
Date: 2017
Abstract: Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic disorder that results in a variety of characteristic manifestations. Prior studies have shown reduced muscle size and global skeletal muscle weakness in children with NF1. This associated weakness can lead to significant challenges impacting on quality of life. Pre-clinical studies using a muscle-specific NF1 knockout mouse have linked this weakness to an underlying primary metabolic deficiency in the muscle. However, the neonatal lethality of this strain prevents analysis of the role of NF1 in adult muscle. In this study, we present the characterization of an inducible muscle-specific NF1 knockout strain (Nf1Pax7i
The application of ceragenins to orthopedic surgery and medicine
Publisher: Wiley
Date: 10-02-2020
DOI: 10.1002/JOR.24615
Abstract: Osteomyelitis and infections associated with orthopedic implants represent a significant burden of disease worldwide. Ceragenins (CSAs) are a relatively new class of small-molecule antimicrobials that target a broad range of Gram-positive and Gram-negative bacteria as well as fungi, viruses, and parasites. This review sets the context of the need for new antimicrobial strategies by cataloging the common pathogens associated with orthopedic infection and highlighting the increasing challenges of managing antibiotic-resistant bacterial strains. It then comparatively describes the antimicrobial properties of CSAs with a focus on the CSA-13 family. More recently developed members of this family such as CSA-90 and CSA-131 may have a particular advantage in an orthopedic setting as they possess secondary pro-osteogenic properties. In this context, we consider several new preclinical studies that demonstrate the utility of CSAs in orthopedic models. Emerging evidence suggests that CSAs are effective against antibiotic-resistant Staphylococcus aureus strains and can prevent the formation of biofilms. There remains considerable scope for developing CSA-based treatments, either as coatings for orthopedic implants or as local or systemic antibiotics to prevent bone infection.
The effect of thermal pasteurization, freeze-drying, and gamma irradiation on donor human milk
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.FOODCHEM.2021.131402
Abstract: The availability of donor human milk (DHM) is currently limited by the volumes that can be thermally pasteurized and kept in long-term cold storage. This study assesses the application of freeze-drying followed by low-dose gamma irradiation of DHM for simplified, safe long-term storage. Solid-phase microextraction (SPME) GC-MS, SDS and native PAGE gel electrophoresis demonstrated that the overall changes in volatile and protein profiles in Holder pasteurized and freeze-dried DHM was negligible compared to the natural variations in DHM. Freeze-dried DHM s les (moisture < 2.2 %) processed with 2 kGy gamma irradiation did not show any significant lipid oxidation end-products and variation in protein profile. Therefore, freeze-drying followed by in-packaging gamma irradiation could be a safe method for pasteurization, convenient storage and delivery of DHM at ambient temperature. These methods may generate a means to create a reserve stock of DHM for emergencies and humanitarian aid.
CSA‐90 reduces periprosthetic joint infection in a novel rat model challenged with local and systemic Staphylococcus aureus
Publisher: Wiley
Date: 11-02-2020
DOI: 10.1002/JOR.24618
Identifying HSV-1 Inhibitors from Natural Compounds via Virtual Screening Targeting Surface Glycoprotein D
Publisher: MDPI AG
Date: 16-03-2022
DOI: 10.3390/PH15030361
Abstract: Herpes simplex virus (HSV) infections are a worldwide health problem in need of new effective treatments. Of particular interest is the identification of antiviral agents that act via different mechanisms compared to current drugs, as these could interact synergistically with first-line antiherpetic agents to accelerate the resolution of HSV-1-associated lesions. For this study, we applied a structure-based molecular docking approach targeting the nectin-1 and herpesvirus entry mediator (HVEM) binding interfaces of the viral glycoprotein D (gD). More than 527,000 natural compounds were virtually screened using Autodock Vina and then filtered for favorable ADMET profiles. Eight top hits were evaluated experimentally in African green monkey kidney cell line (VERO) cells, which yielded two compounds with potential antiherpetic activity. One active compound (1-(1-benzofuran-2-yl)-2-[(5Z)-2H,6H,7H,8H-[1,3] dioxolo[4,5-g]isoquinoline-5-ylidene]ethenone) showed weak but significant antiviral activity. Although less potent than antiherpetic agents, such as acyclovir, it acted at the viral inactivation stage in a dose-dependent manner, suggesting a novel mode of action. These results highlight the feasibility of in silico approaches for identifying new antiviral compounds, which may be further optimized by medicinal chemistry approaches.
Analysis of muscle tissue in vivo using fiber-optic autofluorescence and diffuse reflectance spectroscopy
Publisher: SPIE-Intl Soc Optical Eng
Date: 22-12-2021
Pretreatment with Pamidronate Decreases Bone Formation but Increases Callus Bone Volume in a Rat Closed Fracture Model
Publisher: Springer Science and Business Media LLC
Date: 10-2020
DOI: 10.1007/S00223-019-00615-Z
Abstract: Clinical concerns have been raised over prior exposure to bisphosphonates impairing fracture healing. To model this, groups of male Wistar rats were assigned to saline control or treatment groups receiving 0.15 mg/kg (low dose), 0.5 mg/kg (medium dose), and 5 mg/kg (high dose) Pamidronate (PAM) twice weekly for 4 weeks. At this point, closed fractures were made using an Einhorn apparatus, and bisphosphonate dosing was continued until the experimental endpoint. Specimens were analyzed at 2 and 6 weeks (N = 8 per group per time point). Twice weekly PAM dosing was found to have no effect on early soft callus remodeling at 2 weeks post fracture. At this time point, the highest dose PAM group gave significant increases in bone volume (+ 10%, p < 0.05), bone mineral content (+ 30%, p < 0.01), and bone mineral density (+ 10%, p < 0.01). This PAM dosing regimen showed more substantive effects on hard callus at 6 weeks post fracture, with PAM treatment groups showing + 46-79% increased bone volume. Dynamic bone labeling showed reduced calcein signal in the PAM-treated calluses (38-63%, p < 0.01) and reduced MAR (32-49%, p < 0.01), suggesting a compensatory reduction in bone anabolism. These data support the concept that bisphosphonates lead to profound decreases in bone turnover in fracture repair, however, this does not affect soft callus remodeling.
Targeting Adeno-Associated Virus Vectors for Local Delivery to Fractures and Systemic Delivery to the Skeleton
Publisher: Elsevier BV
Date: 12-2019
Muscle costameric protein, Chisel/Smpx, associates with focal adhesion complexes and modulates cell spreading in vitro via a Rac1/p38 pathway
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.YEXCR.2005.04.006
Abstract: The murine X-linked gene Chisel (Csl/Smpx) encodes a 9-kDa protein that associates in heart and skeletal muscle cells with the costameric cytoskeleton, implicated in maintaining muscle integrity and responses to biomechanical stress. After expression in C2C12 myoblasts, MYC epitope-tagged Csl co-localized with actin networks at peripheral membranes, and with focal adhesion proteins vinculin, paxillin, integrin beta1, and the small GTPase Rac1. Csl could be co-immunoprecipitated with vinculin from extracts of C2C12 cells and native muscle. MYC-Csl induced cell spreading and lamellipodia formation in C2C12 cells at the expense of filopodia, suggestive of modulation of Rac1 activity. Lamellipodia formation was indeed Rac1-dependent, and in MYC-Csl cells replated on fibronectin, Rac1 activity was increased relative to controls. Expression of MYC-Csl led to an increased association between vinculin and p34, a subunit of the Arp2/3 actin nucleation complex, a Rac1-dependent event. Induced cell spreading was also dependent upon p38 kinases that act downstream of Rac1 to control the actin capping activity of heat shock protein 27. Our data suggest that Csl localizes to the costameric cytoskeleton of muscle cells through an association with focal adhesion proteins, where it may participate in regulation of cytoskeletal dynamics through the Rac1-p38 pathway.
Synthesis and Characterization of Bone Binding Antibiotic-1 (BBA-1), a Novel Antimicrobial for Orthopedic Applications
Publisher: MDPI AG
Date: 11-03-2021
DOI: 10.3390/MOLECULES26061541
Abstract: Osteomyelitis and orthopedic infections are major clinical problems, limited by a lack of antibiotics specialized for such applications. In this paper, we describe the design and synthesis of a novel bone-binding antibiotic (BBA-1) and its subsequent structural and functional characterization. The synthesis of BBA-1 was the result of a two-step chemical conjugation of cationic selective antimicrobial-90 (CSA-90) and the bisphosphonate alendronate (ALN) via a heterobifunctional linker. This was analytically confirmed by HPLC, FT-IR, MS and NMR spectroscopy. BBA-1 showed rapid binding and high affinity to bone mineral in an in vitro hydroxyapatite binding assay. Kirby—Baur assays confirmed that BBA-1 shows a potent antibacterial activity against Staphylococcus aureus and methicillin-resistant S. aureus comparable to CSA-90. Differentiation of cultured osteoblasts in media supplemented with BBA-1 led to increased alkaline phosphatase expression, which is consistent with the pro-osteogenic activity of CSA-90. Bisphosphonates, such as ALN, are inhibitors of protein prenylation, however, the amine conjugation of ALN to CSA-90 disrupted this activity in an in vitro protein prenylation assay. Overall, these findings support the antimicrobial, bone-binding, and pro-osteogenic activities of BBA-1. The compound and related agents have the potential to ensure lasting activity against osteomyelitis after systemic delivery.
Ras-MAPK signaling in osteogenic differentiation: Friend or foe?
Publisher: Wiley
Date: 09-2006
DOI: 10.1359/JBMR.060603
A murine model of neurofibromatosis type 1 tibial pseudarthrosis featuring proliferative fibrous tissue and osteoclast‐like cells
Publisher: Wiley
Date: 22-12-2011
DOI: 10.1002/JBMR.528
Abstract: Neurofibromatosis type 1 (NF1) is a common genetic condition caused by mutations in the NF1 gene. Patients often suffer from tissue-specific lesions associated with local double-inactivation of NF1. In this study, we generated a novel fracture model to investigate the mechanism underlying congenital pseudarthrosis of the tibia (CPT) associated with NF1. We used a Cre-expressing adenovirus (AdCre) to inactivate Nf1 in vitro in cultured osteoprogenitors and osteoblasts, and in vivo in the fracture callus of Nf1(flox/flox) and Nf1(flox/-) mice. The effects of the presence of Nf1(null) cells were extensively examined. Cultured Nf1(null)-committed osteoprogenitors from neonatal calvaria failed to differentiate and express mature osteoblastic markers, even with recombinant bone morphogenetic protein-2 (rhBMP-2) treatment. Similarly, Nf1(null)-inducible osteoprogenitors obtained from Nf1 MyoDnull mouse muscle were also unresponsive to rhBMP-2. In both closed and open fracture models in Nf1(flox/flox) and Nf1(flox/-) mice, local AdCre injection significantly impaired bone healing, with fracture union being <50% that of wild type controls. No significant difference was seen between Nf1(flox/flox) and Nf1(flox/-) mice. Histological analyses showed invasion of the Nf1(null) fractures by fibrous and highly proliferative tissue. Mean amounts of fibrous tissue were increased upward of 10-fold in Nf1(null) fractures and bromodeoxyuridine (BrdU) staining in closed fractures showed increased numbers of proliferating cells. In Nf1(null) fractures, tartrate-resistant acid phosphatase-positive (TRAP+) cells were frequently observed within the fibrous tissue, not lining a bone surface. In summary, we report that local Nf1 deletion in a fracture callus is sufficient to impair bony union and recapitulate histological features of clinical CPT. Cell culture findings support the concept that Nf1 double inactivation impairs early osteoblastic differentiation. This model provides valuable insight into the pathobiology of the disease, and will be helpful for trialing therapeutic compounds.
Current challenges and emergent technologies for manufacturing artificial right ventricle to pulmonary artery (RV-PA) cardiac conduits
Publisher: Springer Science and Business Media LLC
Date: 14-02-2019
DOI: 10.1007/S13239-019-00406-5
Abstract: Despite advances in modern surgery, congenital heart disease remains a medical challenge and major cause of infant mortality. Valved conduits are routinely used to surgically correct blood flow in hearts with congenital malformations by connecting the right ventricle to the pulmonary artery (RV-PA). This review explores the current range of RV-PA conduits and describes their strengths and disadvantages. Homografts and xenografts are currently the primary treatment modalities, however both graft types have limited biocompatibility and durability, and present a disease transmission risk. Structural deterioration of a replaced valve can lead to pulmonary valve stenosis and/or regurgitation. Moreover, as current RV-PA conduits are of a fixed size, multiple subsequent operations are required to upsize a valved conduit over a patient's lifetime. We assess emerging biomaterials and tissue engineering techniques with a view to replicating the features of native tissues, including matching the durability and elasticity required for normal fluid flow dynamics. The benefits and limitations of incorporating cellular elements within the biomaterial are also discussed. Present review demonstrates that an alignment of medical and engineering disciplines will be ultimately required to produce a biocompatible and high-functioning artificial conduit.
Optimized Synthesis of Poly(deoxyribose) Isobutyrate, a Viscous Biomaterial for Bone Morphogenetic Protein-2 Delivery
Publisher: American Chemical Society (ACS)
Date: 27-12-2019
Abstract: Injectable and phase-transitioning carriers from natural polysaccharides have great potential for the minimally invasive delivery of therapeutic proteins in the field of bone tissue engineering. In this study, a novel and highly viscous drug carrier was synthesized by a sequential process of deoxyribose polycondensation and esterification. The effect of synthesis parameters on the molecular weight, viscosity, and adhesion of the material was studied and correlated to temperature and time of polycondensation ( T
Improved union and bone strength in a mouse model of NF1 pseudarthrosis treated with recombinant human bone morphogenetic protein-2 and zoledronic acid
Publisher: Wiley
Date: 04-10-2018
DOI: 10.1002/JOR.23672
Abstract: Tibial pseudarthrosis associated with Neurofibromatosis type 1 (NF1) is an orthopedic condition with consistently poor clinical outcomes. Using a murine model that features localized double inactivation of the Nf1 gene in an experimental tibial fracture, we tested the effects of recombinant human bone morphogenetic protein-2 (rhBMP-2) and/or the bisphosphonate zoledronic acid (ZA). Tibiae were harvested at 3 weeks for analysis, at which time there was negligible healing in un-treated control fractures (7% union). In contrast, rhBMP-2 and rhBMP-2/ZA groups showed significantly greater union (87% and 93%, p < 0.01 for both). Treatment with rhBMP-2 led to a 12-fold increase in callus bone volume and this was further increased in the rhBMP-2/ZA group. Mechanical testing of the healed rhBMP-2 and rhBMP-2/ZA fractures showed that the latter group had significantly higher mechanical strength and was restored to that of the un-fractured contralateral leg. Co-treatment with rhBMP-2/ZA also reduced fibrous tissue infiltration at the fracture site compared to rhBMP alone (p = 0.068). These data support the future clinical investigation of this combination of anabolic and anti-resorptive agents for the treatment of NF1 pseudarthrosis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:930-936, 2018.
PTH(1-34) treatment increases bisphosphonate turnover in fracture repair in rats
Publisher: Wiley
Date: 18-05-2015
DOI: 10.1002/JBMR.2424
Abstract: Bisphosphonates (BP) are antiresorptive drugs with a high affinity for bone. Despite the therapeutic success in treating osteoporosis and metabolic bone diseases, chronic BP usage has been associated with reduced repair of microdamage and atypical femoral fracture (AFF). The latter has a poor prognosis, and although anabolic interventions such as teriparatide (PTH(1-34) ) have been suggested as treatment options, there is a limited evidence base in support of their efficacy. Because PTH(1-34) acts to increase bone turnover, we hypothesized that it may be able to increase BP in turnover in the skeleton, which, in turn, may improve bone healing. To test this, we employed a mixture of fluorescent Alexa647-labelled pamidronate (Pam) and radiolabeled (14) C-ZA (zoledronic acid). These traceable BPs were dosed to Wistar rats in models of normal growth and closed fracture repair. Rats were cotreated with saline or 25 μg/kg/d PTH(1-34) , and the effects on BP liberation and bone healing were examined by X-ray, micro-CT, autoradiography, and fluorescent confocal microscopy. Consistent with increased BP remobilization with PTH(1-34) , there was a significant decrease in fluorescence in both the long bones and in the fracture callus in treated animals compared with controls. This was further confirmed by autoradiography for (14) C-ZA. In this model of acute BP treatment, callus bone volume (BV) was significantly increased in fractured limbs, and although we noted significant decreases in callus-bound BP with PTH(1-34) , these were not sufficient to alter this BV. However, increased intracellular BP was noted in resorbing osteoclasts, confirming that, in principle, PTH(1-34) increases bone turnover as well as BP turnover.
L-carnitine supplementation for muscle weakness and fatigue in children with neurofibromatosis type 1: A Phase 2a clinical trial
Publisher: Wiley
Date: 21-06-2021
DOI: 10.1002/AJMG.A.62392
Abstract: Reduced muscle tone, muscle weakness, and physical fatigue can impact considerably on quality of life for children with neurofibromatosis type 1 (NF1). Human muscle biopsies and mouse models of NF1 deficiency in muscle show intramyocellular lipid accumulation, and preclinical data have indicated that L‐carnitine supplementation can ameliorate this phenotype. The aim of this study is to examine whether daily L‐carnitine supplementation is safe and feasible, and will improve muscle strength and reduce fatigue in children with NF1. A 12‐week Phase 2a trial was conducted using 1000 mg daily oral levocarnitine tartrate supplementation. Recruited children were between 8 and 12 years old with a clinical diagnosis of NF1, history of muscle weakness and fatigue, and naïve to L‐carnitine. Primary outcomes were safety (self‐reporting, biochemical testing) and compliance. Secondary outcomes included plasma acylcarnitine profiles, functional measures (muscle strength, long jump, handwriting speed, 6‐minute‐walk test [6MWT]), and parent‐reported questionnaires (PedsQL™, CBCL/6–18). Six children completed the trial with no self‐reported adverse events. Biochemical tests for kidney and liver function were normal, and the average compliance was 95%. Plasma acylcarnitine levels were low, but within a range not clinically linked to carnitine deficiency. For strength measures, there was a mean 53% increase in dorsiflexion strength (95% confidence interval [CI] 8.89–60.75 p = 0.02) and mean 66% increase in plantarflexion strength (95% CI 12.99–134.1 p = 0.03). In terms of muscle performance, there was a mean 10% increase in long jump distance (95% CI 2.97–16.03 p = 0.01) and 6MWT distance (95% CI 5.88–75.45 p = 0.03). Comparison with the 1000 Norms Project data showed a significant improvement in Z‐score for all of these measures. Parent reports showed no negative impact on quality of life, and the perceived benefits led to the majority of in iduals remaining on L‐carnitine after the study. Twelve weeks of L‐carnitine supplementation is safe and feasible in children with NF1, and a Phase 3 trial should confirm the efficacy of treatment.
Combination treatment with growth hormone and zoledronic acid in a mouse model of Osteogenesis imperfecta
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.BONE.2022.116378
Abstract: Osteogenesis imperfecta (OI) or brittle bone disease is a genetic disorder that results in bone fragility. Bisphosphonates such as zoledronic acid (ZA) are used clinically to increase bone mass and reduce fracture risk. Human growth hormone (hGH) has been used to promote long bone growth and forestall short stature in children with OI. The potential for hGH to improve bone quality, particularly in combination with ZA has not been robustly studied. A preclinical study was performed using n = 80 mice split evenly by genotype (WT, Col1a2 Treatment with hGH alone led to an increase in femur length in WT but not OI mice, however bone length was increased in both genotypes with the combination of hGH/ZA. MicroCT showed that hGH/ZA treatment increased cortical BV in both WT (+15%) and OI mice (+14.3%) hGH/ZA were also found to be synergistic in promoting cortical thickness in OI bone. ZA was found to have a considerably greater positive impact on trabecular bone than hGH. ZA was found to suppress bone turnover, and this was rescued by hGH treatment in terms of cortical periosteal perimeter, but not by dynamic bone remodeling. Statistically significant improvements in long bone by microCT did not translate into improvements in mechanical strength in a 4-point bending test, nor did vertebral strength improve in L4 compression testing in WT/OI bone. These data support hGH/ZA combination as a treatment for short stature, however the improvements granted by hGH alone and in combination with ZA on bone quality are modest. Increased periosteal perimeter does show promise in improving bone strength in OI, however a longer treatment time may be required to see effects on bone strength through mechanical testing.
Inducible cell labeling and lineage tracking during fracture repair
Publisher: Wiley
Date: 11-11-2015
DOI: 10.1111/DGD.12184
Abstract: Mouse models incorporating inducible Cre-ERT2/LoxP recombination coupled with sensitive fluorescent reporter lines are being increasingly used to track cell lineages in vivo. In this study we use two inducible reporter strains, Ai9iCol2a1 (Ai9×Col2a1-creERT2) to track contribution of chondrogenic progenitors during bone regeneration in a closed fracture model and Ai9i UBC (Ai9×UBC-creERT2) to examine methods for inducing localized recombination. By comparing with Ai9 littermate controls as well as inducible reporter mice not dosed with tamoxifen, we revealed significant leakiness of the CreERT2 system, particularly in the bone marrow of both lines. These studies highlight the challenges associated with highly sensitive reporters that may be activated without induction in tissues where the CreERT2 fusion is expressed. Examination of the growth plate in the Ai9iCol2a1 strain showed cells of the osteochondral lineage (cell co-staining with chondrocyte and osteoblast markers) labeled with the tdTom reporter. However, no such labeling was noted in healing fractures of Ai9iCol2a1 mice. Attempts to label a single limb using intramuscular injection of 4-hydroxytamoxifen in the Ai9i UBC strain resulted in complete labeling of the entire animal, comparable to intraperitoneal injection. While a challenge to interpret, these data are nonetheless informative regarding the limitations of these inducible reporter models, and justify caution and expansive controls in future studies using such models.
A Bioactive Coating Enhances Bone Allografts in Rat Models of Bone Formation and Critical Defect Repair
Publisher: Wiley
Date: 17-07-2019
DOI: 10.1002/JOR.24409
Abstract: Bone allografts are inferior to autografts for the repair of critical-sized defects. Prior studies have suggested that bone morphogenetic protein-2 (BMP-2) can be combined with allografts to produce superior healing. We created a bioactive coating on bone allografts using polycondensed deoxyribose isobutyrate ester (PDIB) polymer to deliver BMP-2 ± the bisphosphonate zoledronic acid (ZA) and tested its ability to enhance the functional utility of allografts in preclinical Wistar rat models. One ex vivo and two in vivo proof-of-concept studies were performed. First, PDIB was shown to be able to coat bone grafts (BGs). Second, PDIB was used to coat structural allogenic corticocancellous BG with BMP-2 ± ZA ± hydroxyapatite (HA) microparticles and compared with PDIB-coated grafts in a rat muscle pouch model. Next, a rat critical defect model was performed with treatment groups including (i) empty defect, (ii) BG, (iii) collagen sponge + BMP-2, (iv) BG + PDIB/BMP-2, and (v) BG + PDIB/BMP-2/ZA. Key outcome measures included detection of fluorescent bone labels, microcomputed tomography (CT) quantification of bone, and radiographic healing. In the muscle pouch study, BMP-2 did not increase net bone volume measured by microCT, however, fluorescent labeling showed large amounts of new bone. Addition of ZA increased BV by sevenfold (p < 0.01). In the critical defect model, allografts were insufficient to promote reliable union, however, union was achieved in collagen/BMP-2 and all BG/BMP-2 groups. Statement of clinical significance: These data support the concept that PDIB is a viable delivery method for BMP-2 and ZA delivery to enhance the bone forming potential of allografts. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2278-2286, 2019.
The Effects of Thermal Pasteurisation, Freeze-Drying, and Gamma-Irradiation on the Antibacterial Properties of Donor Human Milk
Publisher: MDPI AG
Date: 02-09-2021
Abstract: The most common pasteurisation method used by human milk banks is Holder pasteurisation. This involves thermal processing, which can denature important proteins and can potentially reduce the natural antimicrobial properties found in human milk. This study assesses the application of a hybrid method comprised of freeze-drying followed by low-dose gamma-irradiation for nonthermal donor human milk pasteurisation. Freeze-drying donor human milk followed by gamma-irradiation at 2 kGy was as efficient as Holder pasteurisation in the reduction of bacterial inoculants of Staphylococcus aureus (106 cfu/mL) and Salmonella typhimurium (106 cfu/mL) in growth inhibition assays. These assays also demonstrated that human milk naturally inhibits the growth of bacterial inoculants S. aureus, S. typhimurium, and Escherichia coli. Freeze drying (without gamma-irradiation) did not significantly reduce this natural growth inhibition. By contrast, Holder pasteurisation significantly reduced the milk’s natural antimicrobial effect on S. aureus growth after 6 h (−19.8% p = 0.01). Freeze-dried and then gamma-irradiated donor human milk showed a strong antimicrobial effect across a dose range of 2–50 kGy, with only a minimal growth of S. aureus observed after 6 h incubation. Thus, a hybrid method of freeze-drying followed by 2 kGy of gamma-irradiation preserves antimicrobial properties and enables bulk pasteurisation within sealed packaging of powderised donor human milk. This work forwards a goal of increasing shelf life and simplifying storage and transportation, while also preserving functionality and antimicrobial properties.
Maximizing bone formation in posterior spine fusion using rhBMP-2 and zoledronic acid in wild type and NF1 deficient mice
Publisher: Wiley
Date: 09-04-2014
DOI: 10.1002/JOR.22628
Abstract: Spinal pseudarthrosis is a well described complication of spine fusion surgery in NF1 patients. Reduced bone formation and excessive resorption have been described in NF1 and anti-resorptive agents may be advantageous in these in iduals. In this study, 16 wild type and 16 Nf1(+/-) mice were subjected to posterolateral fusion using collagen sponges containing 5 µg rhBMP-2 introduced bilaterally. Mice were dosed twice weekly with 0.02 mg/kg zoledronic acid (ZA) or sterile saline. The fusion mass was assessed for bone volume (BV) and bone mineral density (BMD) by microCT. Co-treatment using rhBMP-2 and ZA produced a significant increase (p < 0.01) in BV of the fusion mass compared to rhBMP-2 alone in both wild type mice (+229%) and Nf1(+/-) mice (+174%). Co-treatment also produced a significantly higher total BMD of the fusion mass compared to rhBMP-2 alone in both groups (p < 0.01). Despite these gains with anti-resorptive treatment, Nf1(+/-) deficient mice still generated less bone than wild type controls. TRAP staining on histological sections indicated an increased osteoclast surface/bone surface (Oc.S/BS) in Nf1(+/-) mice relative to wild type mice, and this was reduced with ZA treatment.
Local co-delivery of rhBMP-2 and cathepsin K inhibitor L006235 in poly (D, L-lactide-co-glycolide) nanospheres
Publisher: Wiley
Date: 05-10-2017
DOI: 10.1002/JBM.B.33481
Abstract: Cathepsin K inhibitors (CKIs) are an emerging class of drugs that are potent antagonists of osteoclastic activity. We speculated that they may be beneficial in bone tissue engineering, where a stress shielded environment can lead to rapid resorption of new bone. Most CKIs require frequent dosing, so to achieve a sustained release we manufactured polymer nanoparticles encapsulating the CKI L006235 (CKI/nP). CKI/nP and the collagen matrices that were used to deliver them were characterized by electron microscopy and fluorescent confocal microscopy, and data indicated that the particles were evenly distributed throughout the collagen. Elution studies indicated a linear release of the inhibitor from the CKI/nP, with approximately 2% of the drug being released per day. In an in vivo study, mice were implanted with collagen scaffolds containing rhBMP-2 that were loaded with the CKI/nP. Measurement of bone volume (BV) by microCT showed no significant increase with CKI/nP incorporation, and other parameters similarly showed no statistical differences. Cell culture studies confirmed the activity of the drug, even at low concentrations. These data indicate that polymer nanoparticles are an effective method for sustained drug delivery of a CKI, however, this may not be readily translatable to substantively improved bone tissue engineering outcomes. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 136-144, 2017.
Guided growth: Current perspectives and future challenges
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2017
DOI: 10.2106/JBJS.RVW.16.00115
Abstract: * Guided growth by tethering part of the growth plate is an established technique for the correction of frontal angular deformities about the knee in children. * A better understanding of the underlying conditions, factors affecting longitudinal growth, and mechanism of response of the growth plate to retardation forces could lead to improvement and expansion of this technique to other sites and indications. * This review article highlights areas of future research and outlines the possible future of guided growth techniques.
The small muscle-specific protein CSl modifies cell shape and promotes myocyte fusion in an insulin-like growth factor 1-dependent manner
Publisher: Rockefeller University Press
Date: 21-05-2001
Abstract: We have isolated a murine cDNA encoding a 9-kD protein, Chisel (Csl), in a screen for transcriptional targets of the cardiac homeodomain factor Nkx2-5. Csl transcripts were detected in atria and ventricles of the heart and in all skeletal muscles and smooth muscles of the stomach and pulmonary veins. Csl protein was distributed throughout the cytoplasm in fetal muscles, although costameric and M-line localization to the muscle cytoskeleton became obvious after further maturation. Targeted disruption of Csl showed no overt muscle phenotype. However, ectopic expression in C2C12 myoblasts induced formation of lamellipodia in which Csl protein became tethered to membrane ruffles. Migration of these cells was retarded in a monolayer wound repair assay. Csl-expressing myoblasts differentiated and fused normally, although in the presence of insulin-like growth factor (IGF)-1 they showed dramatically enhanced fusion, leading to formation of large dysmorphogenic “myosacs.” The activities of transcription factors nuclear factor of activated T cells (NFAT) and myocyte enhancer–binding factor (MEF)2, were also enhanced in an IGF-1 signaling–dependent manner. The dynamic cytoskeletal localization of Csl and its dominant effects on cell shape and behavior and transcription factor activity suggest that Csl plays a role in the regulatory network through which muscle cells coordinate their structural and functional states during growth, adaptation, and repair.
JNK inhibitor CC-930 reduces fibrosis in a murine model of Nf1-deficient fracture repair
Publisher: University of South Bohemia in Ceske Budejovice
Date: 11-2018
RAP‐011 augments callus formation in closed fractures in rats
Publisher: Wiley
Date: 09-2015
DOI: 10.1002/JOR.22985
Abstract: ACE-011 is a bone anabolic agent generated by fusing the extracellular domain of the Activin Type 2A receptor (ActRIIA) to an IgG-Fc. The orthopedic utility of ACE-011 was investigated using a murine analogue, RAP-011. Initially, a rat closed fracture model was tested using bi-weekly (biw) 10 mg/kg RAP-011. RAP-011 significantly increased callus length and callus bone volume (BV, +43% at 6w, p < 0.01). The polar moment of inertia was calculated to be substantively increased (+80%, p < 0.01), however mechanical bending tests showed a more modest increase in maximum load to failure (+24%, p < 0.05). Histology indicated enhanced appositional bone growth, but it was hypothesized that reduced remodeling, evidenced by decreased serum CTX (-16% at 6w, p < 0.01), could be compromising bone quality in the callus. A second closed fracture study was performed to examine lower "pulse" [RAP-011(p)] and "sustained" [RAP-011(s)] regimens of biw 0.6mg/kg × 2, 0.35mg/kg × 3 and 0.18mg/kg × 2, 0.1mg/kg × 7 respectively, compared with PTH(1-34) (25 μg/kg/d) and vehicle controls. RAP-011 treatments gave modest increases in callus length and callus BV at 6w (p < 0.01), but did not achieve an increase in maximum load over vehicle. In summary, RAP-011 is effective in promoting bone formation during repair, but optimizing callus bone quality will require further investigation.
Sustained Protein Release from a Core-Shell Drug Carrier System Comprised of Mesoporous Nanoparticles and an Injectable Hydrogel.
Publisher: Wiley
Date: 05-11-2018
Abstract: The manufacture of a biocompatible carrier for controlled delivery of bioactive compounds is described. This carrier is composed of a mesoporous silica nanoparticle as core that is homogenously distributed in an injectable hydrogel. For the synthesis of nanoparticles, a one step sol-gel method is developed to produce pores with the range of 100 nm. BMP2 and Fluorescein-conjugated bovine serum albumin is used as proteinaceous agents for measuring release, and is loaded into mesoporous silica nanoparticles at the optimum conditions of 48 h incubation period using 1:10 ratio of protein to nanoparticles. The release of proteins from either mesoporous nanoparticles or hydrogel in idually involves a burst release stage, however the release from the core/shell carrier designed in this study follows a zero order kinetic. In summary, this biomaterial may be favorable for delivery of bioactive compounds such as BMP2 for a range of applications including bone tissue regeneration.
Personalized Baghdadite Scaffolds: Stereolithography, Mechanics and In vivo Testing
Publisher: Elsevier BV
Date: 2020
DOI: 10.2139/SSRN.3737306
Dkk1 KO Mice Treated with Sclerostin Antibody Have Additional Increases in Bone Volume
Publisher: Springer Science and Business Media LLC
Date: 29-05-2018
DOI: 10.1007/S00223-018-0420-6
Abstract: Dickkopf-1 (DKK1) and sclerostin are antagonists of the Wnt/β-catenin pathway and decreased expression of either results in increased bone formation and mass. As both affect the same signaling pathway, we aimed to elucidate the redundancy and/or compensation of sclerostin and DKK1. Weekly sclerostin antibody (Scl-Ab) was used to treat 9-week-old female Dkk1 KO (Dkk1
Induction of periosteal bone formation by intraosseous BMP-2 injection in a mouse model of osteogenesis imperfecta
Publisher: SAGE Publications
Date: 10-2019
DOI: 10.1302/1863-2548.13.190119
Abstract: Surgical interventions are routinely performed on children with osteogenesis imperfecta (OI) to stabilize long bones, often post fracture. We speculated that a combination of intramedullary reaming and intraosseous injection of recombinant bone morphogenetic protein-2 (BMP-2) could enhance periosteal ossification and ultimately cortical thickness and strength. This approach was conceptually tested in a preclinical model of genetic bone fragility. Six experimental groups were tested including no treatment, intramedullary reaming, and reaming with 5 µg BMP-2 injection performed in the tibiae of both wild type (WT) and Col1a2 G610C/+ (OI, Amish mutation) mice. Bone formation was examined at a two-week time point in ex vivo specimens by micro-computed tomography (microCT) analysis and histomorphometry with a dynamic bone label. MicroCT data illustrated increases in tibial cortical thickness with intramedullary reaming alone (Saline) and reaming plus BMP-2 injection (BMP-2) compared to no intervention controls. In the OI mice, the periosteal bone increase was not statistically significant with Saline but there was an increase of +192% (p = 0.053) with BMP-2 injection. Dynamic histomorphometry on calcein label was used to quantify new woven bone formation while BMP-2 induced greater bone formation than Saline, the anabolic response was blunted overall in the OI groups. These data indicate that targeting the intramedullary compartment via reaming and intraosseous BMP-2 delivery can lead to gains in cortical bone parameters. It is suggested that the next step is to validate safety and functional improvements in a clinical OI setting.
The anabolic and catabolic responses in bone repair
Publisher: British Editorial Society of Bone & Joint Surgery
Date: 04-2007
DOI: 10.1302/0301-620X.89B4.18301
Abstract: The literature on fracture repair has been reviewed. The traditional concepts of delayed and nonunion have been examined in terms of the phased and balanced anabolic and catabolic responses in bone repair. The role of medical manipulation of these inter-related responses in the fracture healing have been considered.
Rescue of High Glucose Impairment of Cultured Human Osteoblasts Using Cinacalcet and Parathyroid Hormone
Publisher: Springer Science and Business Media LLC
Date: 08-02-2023
DOI: 10.1007/S00223-023-01062-7
Abstract: Patients with type 2 diabetes mellitus (T2DM) experience a higher risk of fractures despite paradoxically exhibiting normal to high bone mineral density (BMD). This has drawn into question the applicability to T2DM of conventional fracture reduction treatments that aim to retain BMD. In a primary human osteoblast culture system, high glucose levels (25 mM) impaired cell proliferation and matrix mineralization compared to physiological glucose levels (5 mM). Treatment with parathyroid hormone (PTH, 10 nM), a bone anabolic agent, and cinacalcet (CN, 1 µM), a calcimimetic able to target the Ca 2+ -sensing receptor (CaSR), were tested for their effects on proliferation and differentiation. Strikingly, CN+PTH co-treatment was shown to promote cell growth and matrix mineralization under both physiological and high glucose conditions. CN+PTH reduced apoptosis by 0.9-fold/0.4-fold as measured by Caspase-3 activity assay, increased alkaline phosphatase (ALP) expression by 1.5-fold/twofold, increased the ratio of nuclear factor κ-B ligand (RANKL) to osteoprotegerin (OPG) by 2.1-fold/1.6-fold, and increased CaSR expression by 1.7-fold/4.6-fold (physiological glucose/high glucose). Collectively, these findings indicate a potential for CN+PTH combination therapy as a method to ameliorate the negative impact of chronic high blood glucose on bone remodeling.
From process to progress—2017 International Conference on Neurofibromatosis 1, Neurofibromatosis 2 and Schwannomatosis
Publisher: Wiley
Date: 25-03-2019
DOI: 10.1002/AJMG.A.61112
Preclinical models for orthopedic research and bone tissue engineering.
Publisher: Wiley
Date: 19-12-2017
DOI: 10.1002/JOR.23824
Abstract: In this review, we broadly define and discuss the preclinical rodent models that are used for orthopedics and bone tissue engineering. These range from implantation models typically used for biocompatibility testing and high-throughput drug screening, through to fracture and critical defect models used to model bone healing and severe orthopedic injuries. As well as highlighting the key methods papers describing these techniques, we provide additional commentary based on our substantive practical experience with animal surgery and in vivo experimental design. This review also briefly touches upon the descriptive and functional outcome measures and power calculations that are necessary for an informative study. Obtaining informative and relevant research outcomes can be very dependent on the model used, and we hope this evaluation of common models will serve as a primer for new researchers looking to undertake preclinical bone studies. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:832-840, 2018.
Biodegradable poly(α-hydroxy acid) polymer scaffolds for bone tissue engineering
Publisher: Wiley
Date: 02-02-2010
DOI: 10.1002/JBM.B.31588
Abstract: Synthetic graft materials are emerging as a viable alternative to autogenous bone graft and bone allograft for the treatment of critical-sized bone defects. These materials can be osteoconductive but are rarely intrinsically osteogenic, although this can be greatly enhanced by the application of bone morphogenetic proteins (BMPs). This review will discuss the versatility of biodegradable poly(alpha-hydroxy acids) for the delivery of BMPs for bone tissue engineering. Poly(alpha-hydroxy acids) have a considerable potential for customization and adaptability via modification of design parameters, including scaffold architecture, composition, and biodegradability. Different fabrication techniques will also be discussed.
Decreased Bone Mineral Density in Neurofibromatosis Type 1
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2007
Bisphosphonate‐laden acrylic bone cement: Mechanical properties, elution performance, and in vivo activity
Publisher: Wiley
Date: 27-05-2008
DOI: 10.1002/JBM.B.31130
Abstract: Cemented total hip replacements generally fail after 10-20 years, often due to implant loosening from bone resorption. Bisphosphonates such as zoledronic acid (ZA) and pamidronate (PAM) are potent inhibitors of bone resorption. The local delivery of bisphosphonates via acrylic bone cement could decrease osteolysis and prolong implant lifespan. Conflicting studies suggest that bisphosphonate loading may or may not reduce the mechanical properties of acrylic bone cement. We assayed acrylic bone cement laden with ZA or PAM at different concentrations and diluent volumes. Four-point bend testing and compressive testing indicated that high volumes of diluent (with or without bisphosphonate) significantly reduced bending modulus and compressive strength. Radiography and electron microscopy indicated that high diluent volumes generated abnormal acrylic bone cement structure. After 6 weeks of incubation in saline, only 0.9% w/w of the total bisphosphonate incorporated in acrylic bone cement eluted in vitro, indicating a slow elution rate. In vivo testing was performed using a rat model. Cement cylinders were inserted into incisions in rat distal femora and ZA delivered locally (via elution from acrylic bone cement) or systemically (via injection). At 4 weeks postoperatively, dual energy X-ray absorptiometry demonstrated no significant increase in local bone mineral density (BMD) adjacent to ZA-laden implants. In contrast, systemic ZA delivery (0.1 mg/kg) led to a large (48.6%) and significant increase in BMD. Thus, systemic delivery appears more effective than local delivery.
Biopolymer‐Based Multilayer Microparticles for Probiotic Delivery to Colon
Publisher: Wiley
Date: 03-03-2022
Abstract: The potential health benefits of probiotics may not be realized because of the substantial reduction in their viability during food storage and gastrointestinal transit. Microencapsulation has been successfully utilized to improve the resistance of probiotics to critical conditions. Owing to the unique properties of biopolymers, they have been prevalently used for microencapsulation of probiotics. However, majority of microencapsulated products only contain a single layer of protection around probiotics, which is likely to be inferior to more sophisticated approaches. This review discusses emerging methods for the multilayer encapsulation of probiotic using biopolymers. Correlations are drawn between fabrication techniques and the resultant microparticle properties. Subsequently, multilayer microparticles are categorized based on their layer designs. Recent reports of specific biopolymeric formulations are examined regarding their physical and biological properties. In particular, animal models of gastrointestinal transit and disease are highlighted, with respect to trials of multilayer microencapsulated probiotics. To conclude, novel materials and approaches for fabrication of multilayer structures are highlighted.
Effect of collagen‐glycosaminoglycan scaffold pore size on matrix mineralization and cellular behavior in different cell types
Publisher: Wiley
Date: 10-2015
DOI: 10.1002/JBM.A.35567
Abstract: We have previously examined osteoblast behavior on porous collagen-glycosaminoglycan (CG) scaffolds with a range of mean pore sizes demonstrating superior cell attachment and migration in scaffolds with the largest pores (325 μm). Scaffolds provide a framework for construct development therefore, it is crucial to identify the optimal pore size for augmented tissue formation. Utilizing the same range of scaffolds (85 μm - 325 μm), this study aimed to examine the effects of mean pore size on subsequent osteoblast differentiation and matrix mineralization, and to understand the mechanism by which pore size influences behavior of different cell types. Consequently, primary mesenchymal stem cells (MSCs) were assessed and their behavior compared to osteoblasts. Results demonstrated that scaffolds with the largest pore size (325 μm) facilitated improved osteoblast infiltration, earlier expression of mature bone markers osteopontin (OPN) and osteocalcin (OCN), and increased mineralization. MSCs responded similarly to osteoblasts whereby cell attachment and scaffold infiltration improved with increasing pore size. However, MSCs showed reduced cell motility, proliferation, and scaffold infiltration compared to osteoblasts. This was associated with differences in the profile of integrin subunits (α2) and collagen receptors (CD44), indicating that osteoblasts have a stronger affinity for CG scaffolds compared to MSCs. In summary, these results reveal how larger pores promote improved cell infiltration, essential for construct development, however the optimal scaffold pore size can be cell type specific. As such, this study highlights a necessity to tailor both scaffold micro-architecture and cell-type when designing constructs for successful bone tissue engineering applications.
A green process for the purification of biodegradable poly(β-hydroxybutyrate)
Publisher: Elsevier BV
Date: 05-2018
Sclerostin Antibody Augments the Anabolic Bone Formation Response in a Mouse Model of Mechanical Tibial Loading
Publisher: Wiley
Date: 29-11-2017
DOI: 10.1002/JBMR.3330
Abstract: Decreased activity or expression of sclerostin, an endogenous inhibitor of Wnt/β-catenin signaling, results in increased bone formation and mass. Antibodies targeting and neutralizing sclerostin (Scl-Ab) have been shown to increase bone mass and reduce fracture risk. Sclerostin is also important in modulating the response of bone to changes in its biomechanical environment. However, the effects of Scl-Ab on mechanotransduction are unclear, and it was speculated that the loading response may be altered for in iduals receiving Scl-Ab therapy. To address this, we carried out a 2-week study of tibial cyclic compressive loading on C57Bl/6 mice treated with vehicle or 100 mg/kg/wk Scl-Ab. Increases in bone volume, density, and dynamic bone formation were found with loading, and the anabolic response was further increased by the combination of load and Scl-Ab. To investigate the underlying mechanism, gene profiling by RNA sequencing (RNAseq) was performed on tibias isolated from mice from all four experimental groups. Major alterations in Wnt/β-catenin gene expression were found with tibial loading, however not with Scl-Ab treatment alone. Notably, the combination of load and Scl-Ab elicited a synergistic response from a number of specific Wnt-related and mechanotransduction factors. An unexpected finding was significant upregulation of factors in the Rho GTPase signaling pathway with combination treatment. In summary, combination therapy had a more profound anabolic response than either Scl-Ab or loading treatment alone. The Wnt/β-catenin and Rho GTPase pathways were implicated within bone mechanotransduction and support the concept that bone mechanotransduction is likely to encompass a number of interconnected signaling pathways. © 2017 American Society for Bone and Mineral Research.
The contribution of different cell lineages to bone repair: Exploring a role for muscle stem cells
Publisher: Elsevier BV
Date: 2009
DOI: 10.1016/J.DIFF.2008.09.007
Abstract: An anabolic response driven by osteoblasts is critical for the process of bone healing. Current evidence suggests that these osteoblasts may arise from multiple tissue types and cell lineages. Stem cells present in the bone marrow, periosteum, local soft tissues, vasculature, and/or circulation have been shown to have osteogenic potential. Transplanted cells from these sources have also been shown to incorporate into induced ectopic bone or repaired bone. While these experiments demonstrate the latent capacity of different lineages to assume an osteoblastic phenotype under pro-osteogenic conditions, the actual contribution of the different lineages to various repair situations in vivo remains unclear. This review explores the data arising from different bone formation and repair models. We propose a model suggesting that cells arising from the local tissues, particularly muscle cells, may play an important role in fracture repair under situations where the periosteal and/or bone marrow progenitor populations are depleted.
Approaches to Treating NF1 Tibial Pseudarthrosis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2013
Curative Cell and Gene Therapy for Osteogenesis Imperfecta
Publisher: Wiley
Date: 17-04-2022
DOI: 10.1002/JBMR.4549
Abstract: Osteogenesis imperfecta (OI) describes a series of genetic bone fragility disorders that can have a substantive impact on patient quality of life. The multidisciplinary approach to management of children and adults with OI primarily involves the administration of antiresorptive medication, allied health (physiotherapy and occupational therapy), and orthopedic surgery. However, advances in gene editing technology and gene therapy vectors bring with them the promise of gene‐targeted interventions to provide an enduring or perhaps permanent cure for OI. This review describes emergent technologies for cell‐ and gene‐targeted therapies, major hurdles to their implementation, and the prospects of their future success with a focus on bone disorders. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Molecular recognition of macrocyclic peptidomimetic inhibitors by HIV-1 protease.
Publisher: American Chemical Society (ACS)
Date: 06-1999
DOI: 10.1021/BI990174X
Local delivery of recombinant human bone morphogenetic proteins and bisphosphonate via sucrose acetate isobutyrate can prevent femoral head collapse in Legg-Calve-Perthes disease: a pilot study in pig
Publisher: Springer Science and Business Media LLC
Date: 04-01-2014
JNK inhibitors increase osteogenesis in Nf1-deficient cells
Publisher: Elsevier BV
Date: 12-2011
DOI: 10.1016/J.BONE.2011.09.043
Abstract: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that is associated with a variety of manifestations, including orthopedic complications such as scoliosis and tibial pseudarthrosis. Orthopedic management of these skeletal complications is rendered more challenging due to a lack of standardized adjunctive pharmacotherapies. NF1 leads to disruption of the canonical Ras/Raf-1/MEK/ERK axis, and this has been associated with defects in bone anabolism. The roles of other non-canonical Ras effector pathways, such as the c-Jun N-terminal Kinase (JNK) pathway, are less well understood. In this study we examine the effects of an anthrapyrazolone inhibitor of JNK (SP600125) on inducible osteoprogenitors as well as Nf1-deficient and Nf1-null primary osteoblasts. C2C12 cells, which are highly responsive to rhBMP-2, were examined with exogenous rhBMP-2 and a range of SP600125 doses. Based on the expression of early and late bone markers and matrix mineralization, 10 μM SP600125 was found to be pro-osteogenic whether delivered concurrent with or following 2 days of rhBMP-2 treatment. Aberrant JNK activity was identified in Nf1-deficient osteoprogenitors (increased rhBMP-2 induced phospho-c-Jun) and in Nf1-null mature osteoblasts (increased total c-Jun). Next, SP600125 was used to treat these cells and was found to facilitate osteogenesis in Nf1-deficient osteoprogenitors, and in Nf1-null osteoblasts when given in conjunction with rhBMP-2. Outcome measures included alkaline phosphatase activity, matrix mineralization, and osteogenic gene expression. In summary, JNK inhibitors represent a class of potentially useful adjunctive agents for orthopedic medicine, particularly in the context of NF1.
Simulating Inflammation in a Wound Microenvironment Using a Dermal Wound-on-a-Chip Model.
Publisher: Wiley
Date: 04-12-2018
Abstract: Considerable progress has been made in the field of microfluidics to develop complex systems for modeling human skin and dermal wound healing processes. While microfluidic models have attempted to integrate multiple cell types and/or 3D culture systems, to date they have lacked some elements needed to fully represent dermal wound healing. This paper describes a cost-effective, multicellular microfluidic system that mimics the paracrine component of early inflammation close to normal wound healing. Collagen and Matrigel are tested as materials for coating and adhesion of dermal fibroblasts and human umbilical vein endothelial cells (HUVECs). The wound-on-chip model consists of three interconnecting channels and is able to simulate wound inflammation by adding tumor necrosis factor alpha (TNF-α) or by triculturing with macrophages. Both the approaches significantly increase IL-1β, IL-6, IL-8 in the supernatant (p < 0.05), and increases in cytokine levels are attenuated by cotreatment with an anti-inflammatory agent, Dexamethasone. Incorporation of M1 and M2 macrophages cocultured with fibroblasts and HUVECs leads to a stimulation of cytokine production as well as vascular structure formation, particularly with M2 macrophages. In summary, this wound-on-chip system can be used to model the paracrine component of the early inflammatory phase of wound healing and has the potential for the screening of anti-inflammatory compounds.
Spatial control of bone formation using a porous polymer scaffold co-delivering anabolic rhBMP-2 and anti-resorptive agents
Publisher: European Cells and Materials
Date: 31-01-2014
DOI: 10.22203/ECM.V027A08
Abstract: Current clinical delivery of recombinant human bone morphogenetic proteins (rhBMPs) utilises freeze-dried collagen. Despite effective new bone generation, rhBMP via collagen can be limited by significant complications due to inflammation and uncontrolled bone formation. This study aimed to produce an alternative rhBMP local delivery system to permit more controllable and superior rhBMP-induced bone formation. Cylindrical porous poly(lactic-co-glycolic acid) (PLGA) scaffolds were manufactured by thermally-induced phase separation. Scaffolds were encapsulated with anabolic rhBMP-2 (20 µg) ± anti-resorptive agents: zoledronic acid (5 µg ZA), ZA pre-adsorbed onto hydroxyapatite microparticles, (5 µg ZA/2% HA) or IkappaB kinase (IKK) inhibitor (10 µg PS-1145). Scaffolds were inserted in a 6-mm critical-sized femoral defect in Wistar rats, and compared against rhBMP-2 via collagen. The regenerate region was examined at 6 weeks by 3D microCT and descriptive histology. MicroCT and histology revealed rhBMP-induced bone was more restricted in the PLGA scaffolds than collagen scaffolds (-92.3% TV, p < 0.01). The regenerate formed by PLGA + rhBMP-2/ZA/HA showed comparable bone volume to rhBMP-2 via collagen, and bone mineral density was +9.1% higher (p < 0.01). Local adjunct ZA/HA or PS-1145 significantly enhanced PLGA + rhBMP-induced bone formation by +78.2% and +52.0%, respectively (p ≤ 0.01). Mechanistically, MG-63 human osteoblast-like cells showed cellular invasion and proliferation within PLGA scaffolds. In conclusion, PLGA scaffolds enabled superior spatial control of rhBMP-induced bone formation over clinically-used collagen. The PLGA scaffold has the potential to avoid uncontrollable bone formation-related safety issues and to customise bone shape by scaffold design. Moreover, local treatment with anti-resorptive agents incorporated within the scaffold further augmented rhBMP-induced bone formation.
Dynamic flow and shear stress as key parameters for intestinal cells morphology and polarization in an organ-on-a-chip model
Publisher: Springer Science and Business Media LLC
Date: 16-10-2021
DOI: 10.1007/S10544-021-00591-Y
Abstract: Gut-on-a-chip microfluidic devices have emerged as versatile and practical systems for modeling the human intestine in vitro . Cells cultured under microfluidic conditions experience the effect of shear stress, used as a biomechanical cue to promote a faster cell polarization in Caco-2 cells when compared with static culture conditions. However, published systems to date have utilized a constant flow rate that fails to account for changes in cell shear stress ( $${\\tau }_{c}$$ τ c ) resulting from changes in cell elongation that occur with differentiation. In this study, computational fluid dynamics (CFD) simulations predict that cells with villi-like morphology experience a $${\\tau }_{c}$$ τ c higher than bulge-like cells at the initial growth stages. Therefore, we investigated the use of a dynamic flow rate to maintain a constant $${\\tau }_{c}$$ τ c across the experiment. Microscopic assessment of cell morphology and dome formation confirmed the initiation of Caco-2 polarization within three days. Next, adopting our dynamic approach, we evaluated whether the following decreased flow could still contribute to complete cell differentiation if compared with the standard constant flow methodology. Caco-2 cells polarized under both conditions, secreted mucin-2 and villin and formed tight junctions and crypt-villi structures. Gene expression was not impacted using the dynamic flow rate. In conclusion, our dynamic flow approach still facilitates cell differentiation while enabling a reduced consumption of reagents.
Distal tibial fracture repair in a neurofibromatosis type 1-deficient mouse treated with recombinant bone morphogenetic protein and a bisphosphonate
Publisher: British Editorial Society of Bone & Joint Surgery
Date: 08-2011
DOI: 10.1302/0301-620X.93B8.25940
Abstract: Congenital pseudarthrosis of the tibia is an uncommon manifestation of neurofibromatosis type 1 (NF1), but one that remains difficult to treat due to anabolic deficiency and catabolic excess. Bone grafting and more recently recombinant human bone morphogenetic proteins (rhBMPs) have been identified as pro-anabolic stimuli with the potential to improve the outcome after surgery. As an additional pharmaceutical intervention, we describe the combined use of rhBMP-2 and the bisphosphonate zoledronic acid in a mouse model of NF1-deficient fracture repair. Fractures were generated in the distal tibiae of neurofibromatosis type 1-deficient (Nf1 +/− ) mice and control mice. Fractures were open and featured periosteal stripping. All mice received 10 μg rhBMP-2 delivered in a carboxymethylcellulose carrier around the fracture as an anabolic stimulus. Bisphosphonate-treated mice also received five doses of 0.02 mg/kg zoledronic acid given by intraperitoneal injection. When only rhBMP but no zoledronic acid was used to promote repair, 75% of fractures in Nf1 +/− mice remained ununited at three weeks compared with 7% of controls (p 0.001). Systemic post-operative administration of zoledronic acid halved the rate of ununited fractures to 37.5% (p 0.07). These data support the concept that preventing bone loss in combination with anabolic stimulation may improve the outcome following surgical treatment for children with congenital pseudarthoris of the tibia and NF1.
Clinical Evidence for the Benefits of Burosumab Therapy for X-Linked Hypophosphatemia (XLH) and Other Conditions in Adults and Children
Publisher: Frontiers Media SA
Date: 28-05-2020
Models of tibial fracture healing in normal and Nf1‐deficient mice
Publisher: Wiley
Date: 08-2008
DOI: 10.1002/JOR.20628
Abstract: Delayed union and nonunion are common complications associated with tibial fractures, particularly in the distal tibia. Existing mouse tibial fracture models are typically closed and middiaphyseal, and thus poorly recapitulate the prevailing conditions following surgery on a human open distal tibial fracture. This report describes our development of two open tibial fracture models in the mouse, where the bone is broken either in the tibial midshaft (mid-diaphysis) or in the distal tibia. Fractures in the distal tibial model showed delayed repair compared to fractures in the tibial midshaft. These tibial fracture models were applied to both wild-type and Nf1-deficient (Nf1+/-) mice. Bone repair has been reported to be exceptionally problematic in human NF1 patients, and these patients can also spontaneously develop tibial nonunions (known as congenital pseudarthrosis of the tibia), which are recalcitrant to even vigorous intervention. pQCT analysis confirmed no fundamental differences in cortical or cancellous bone in Nf1-deficient mouse tibiae compared to wild-type mice. Although no difference in bone healing was seen in the tibial midshaft fracture model, the healing of distal tibial fractures was found to be impaired in Nf1+/- mice. The histological features associated with nonunited Nf1+/- fractures were variable, but included delayed cartilage removal, disproportionate fibrous invasion, insufficient new bone anabolism, and excessive catabolism. These findings imply that the pathology of tibial pseudarthrosis in human NF1 is complex and likely to be multifactorial.
A benign process for the recovery of solanesol from tomato leaf waste
Publisher: Elsevier BV
Date: 04-2019
Extraction of phytochemicals from tomato leaf waste using subcritical carbon dioxide
Publisher: Elsevier BV
Date: 10-2019
Developmental dosing with a MEK inhibitor (PD0325901) rescues myopathic features of the muscle-specific but not limb-specific Nf1 knockout mouse
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.YMGME.2018.02.009
Abstract: Neurofibromatosis Type 1 (NF1) is a common autosomal dominant genetic disorder While NF1 is primarily associated with predisposition for tumor formation, muscle weakness has emerged as having a significant impact on quality of life. NF1 inactivation is linked with a canonical upregulation Ras-MEK-ERK signaling. This in this study we tested the capacity of the small molecule MEK inhibitor PD0325901 to influence the intramyocellular lipid accumulation associated with NF1 deficiency. Established murine models of tissue specific Nf1 deletion in skeletal muscle (Nf1
The risk of infectious pathogens in breast-feeding, donated human milk and breast milk substitutes
Publisher: Cambridge University Press (CUP)
Date: 16-06-2020
DOI: 10.1017/S1368980020000555
Abstract: This review collates the published reports that focus on microbial and viral illnesses that can be transmitted by breast milk, donor milk and powdered infant formula (PIF). In this context, we attempt to define a risk framework encompassing those hazards, exposure scenarios, vulnerability and protective factors. A literature search was performed for reported cases of morbidity and mortality associated with different infant feeding modes. Exclusive breast-feeding is the recommended for infant feeding under 6 months, or failing that, provision of donated human milk. However, the use of PIF remains high despite its intrinsic and extrinsic risk of microbial contamination, as well as the potential for adverse physiological effects, including infant gut dysbiosis. Viable pathogen transmission via breast-feeding or donor milk (pasteurised and unpasteurised) is rare. However, transmission of HIV and human T-cell lymphotropic virus-1 is a concern for breast-feeding mothers, particularly for mothers undertaking a mixed feeding mode (PIF and breast-feeding). In PIF, intrinsic and extrinsic microbial contamination, such as Cronobacter and Salmonella , remain significant identifiable causes of infant morbidity and mortality. Disease transmission through breast-feeding or donor human milk is rare, most likely owing to its complex intrinsically protective composition of human milk and protection of the infant gut lining. Contamination of PIF and the morbidity associated with this is likely underappreciated in terms of community risk. A better system of safe donor milk sharing that also establishes security of supply for non-hospitalised healthy infants in need of breast milk would reduce the reliance on PIF.
Myoblast sensitivity and fibroblast insensitivity to osteogenic conversion by BMP-2 correlates with the expression of Bmpr-1a.
Publisher: Springer Science and Business Media LLC
Date: 15-05-2009
Strategies for senolytic drug discovery
Publisher: Wiley
Date: 07-08-2023
DOI: 10.1111/ACEL.13948
Abstract: Senolytics are a category of drugs that reduce the impact of cellular senescence, an effect associated with a range of chronic and age‐related diseases. Since the discovery of the first senolytics in 2015, the number of known senolytic agents has grown dramatically. This review discusses the broad categories of known senolytics—kinase inhibitors, Bcl‐2 family protein inhibitors, naturally occurring polyphenols, heat shock protein inhibitors, BET family protein inhibitors, P53 stabilizers, repurposed anti‐cancer drugs, cardiac steroids, PPAR‐alpha agonists, and antibiotics. The approaches used to screen for new senolytics are articulated including a range of methods to induce senescence, different target cell types, various senolytic assays, and markers. The choice of methods can greatly influence the outcomes of a screen, with high‐quality screens featuring robust systems, adequate controls, and extensive validation in alternate assays. Recent advances in single‐cell analysis and computational methods for senolytic identification are also discussed. There is significant potential for further drug discovery, but this will require additional research into drug targets and mechanisms of actions and their subsequent rigorous evaluation in pre‐clinical models and human trials.
Dietary intervention rescues myopathy associated with neurofibromatosis type 1
Publisher: Oxford University Press (OUP)
Date: 08-12-2017
DOI: 10.1093/HMG/DDX423
Abstract: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder with complex symptomology. In addition to a predisposition to tumors, children with NF1 can present with reduced muscle mass, global muscle weakness, and impaired motor skills, which can have a significant impact on quality of life. Genetic mouse models have shown a lipid storage disease phenotype may underlie muscle weakness in NF1. Herein we confirm that biopsy specimens from six in iduals with NF1 similarly manifest features of a lipid storage myopathy, with marked accumulation of intramyocellular lipid, fibrosis, and mononuclear cell infiltrates. Intramyocellular lipid was also correlated with reductions in neurofibromin protein expression by western analysis. An RNASeq profile of Nf1null muscle from a muscle-specific Nf1 knockout mouse (Nf1MyoD-/-) revealed alterations in genes associated with glucose regulation and cell signaling. Comparison by lipid mass spectrometry demonstrated that Nf1null muscle specimens were enriched for long chain fatty acid (LCFA) containing neutral lipids, such as cholesterol esters and triacylglycerides, suggesting fundamentally impaired LCFA metabolism. The subsequent generation of a limb-specific Nf1 knockout mouse (Nf1Prx1-/-) recapitulated all observed features of human NF1 myopathy, including lipid storage, fibrosis, and muscle weakness. Collectively, these insights led to the evaluation of a dietary intervention of reduced LCFAs, and enrichment of medium-chain fatty acids (MCFAs) with L-carnitine. Following 8-weeks of dietary treatment, Nf1Prx1-/- mice showed a 45% increase in maximal grip strength, and a 71% reduction in intramyocellular lipid staining compared with littermates fed standard chow. These data link NF1 deficiency to fundamental shifts in muscle metabolism, and provide strong proof of principal that a dietary intervention can ameliorate symptoms.
Bisphosphonate action: revelations and deceptions from in vitro studies
Publisher: Elsevier BV
Date: 08-2007
DOI: 10.1002/JPS.20904
Sclerostin antibody enhances bone formation in a rat model of distraction osteogenesis
Publisher: Wiley
Date: 02-2018
DOI: 10.1002/JOR.23726
Abstract: Neutralizing monoclonal sclerostin antibodies are effective in promoting bone formation at a systemic level and in orthopedic scenarios including closed fracture repair. In this study we examined the effects of sclerostin antibody (Scl-Ab) treatment on regenerate volume, density, and strength in a rat model of distraction osteogenesis. Surgical osteotomy was performed on 179 Sprague Dawley rats. After 1 week, rats underwent distraction for 2 weeks, followed by 6 weeks for consolidation. Two treatment groups received biweekly subcutaneous Scl-AbIII (a rodent form of Scl-Ab 25 mg/kg), either from the start of distraction onward or restricted to the consolidation phase. These groups were compared to controls receiving saline. Measurement modalities included longitudinal DXA, ex vivo QCT, and microCT, tissue histology, and biomechanical four-point bending tests. Bone volume was increased in both Scl-Ab treatments regimens by the end of consolidation (+26-38%, p < 0.05), as assessed by microCT. This was associated with increased mineral apposition. Importantly, Scl-Ab led to increased strength in united bones, and this reached statistical significance in animals receiving Scl-Ab during consolidation only (+177%, p < 0.01, maximum load to failure). These data demonstrate that Scl-Ab treatment increases bone formation, leading to regenerates with higher bone volume and improved strength. Our data also suggest that the optimal effects of Scl-Ab treatment are achieved in the latter stages of distraction osteogenesis. These findings support further investigation into the potential clinical application of sclerostin antibody to augment bone distraction, such as limb lengthening, particularly in the prevention of refracture. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1106-1113, 2018.
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View Funded ActivityLinkage Projects - Grant ID: LP190100143
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