ORCID Profile
0000-0002-7188-0928
Current Organisation
University of Adelaide
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Publisher: Wiley
Date: 06-2010
Publisher: Wiley
Date: 29-05-2015
DOI: 10.1002/JBM.A.35484
Abstract: The study aimed to determine the effects of parthenolide (PAR) on bone volume (BV) and bone surface resorption as assessed by live-animal microcomputed tomography (μCT) and possible osteocyte death as indicated by empty lacunae histologically in polyethylene (PE) particle-induced calvarial osteolysis in mice. Baseline μCT scans were conducted 7 days preimplantation of 2 × 10(8) PE particles/mL over the calvariae (day 0). PAR at 1 mg/kg/day was subcutaneously injected on days 0, 4, 7, and 10. At day 14, BV and surface resorption was analyzed with μCT. Calvarial tissue was processed for histomorphometric osteocyte evaluation. Serum was analyzed for type-1 carboxy-terminal collagen crosslinks (CTX-1) and osteoclast associated receptor (OSCAR) levels by ELISA. PE significantly decreased BV (p = 0.0368), increased surface bone resorption area (p = 0.0022), and increased the percentage of empty lacunae (p = 0.0043). Interestingly, PAR significantly reduced the resorption surface area (p = 0.0022) and the percentage of empty osteocyte lacunae (p = 0.0087) in the PE-calvariae, but it did not affect BV, serum CTX-1 or OSCAR levels. The ability of PAR to inhibit PE-induced surface bone erosion may better reflect the in vivo situation, where bone resorption occurs on the surface at the bone-implant interface and may also be related to the role of osteocytes in this pathology.
Publisher: Elsevier BV
Date: 03-2016
DOI: 10.1016/J.ACTBIO.2016.01.016
Abstract: Periprosthetic osteolysis (PO) leading to aseptic loosening, is the most common cause of failure of total hip replacement (THR) in the mid- to long-term. Polyethylene (PE) particulates from the wear of prosthesis liners are bioactive and are implicated in the initiation and or progression of osteolysis. Evidence exists that cells of the osteoblast/osteocyte lineage are affected by PE particles and contribute to the catabolic response by promoting osteoclastic bone resorption. In this study, we hypothesised that osteocytes contribute directly to PO by removing bone from their perilacunar matrix. Osteocyte responses to ultra-high molecular weight PE (UHMWPE) particles were examined in vitro in human primary osteocyte-like cultures, in vivo in the mouse calvarial osteolysis model, and in the acetabulum of patients undergoing revision total hip replacement (THR) surgery for PO. Osteocytes exposed to UHMWPE particles showed upregulated expression of catabolic markers, MMP-13, carbonic anhydrase 2 (CA2), cathepsin K (CTSK) and tartrate resistant acid phosphatase (TRAP), with no effect on cell viability, as assessed by Caspase 3 activity. Consistent with this catabolic activity causing perilacunar bone loss, histological analysis of calvarial sections from mice exposed to UHMWPE revealed a significant (p<0.001) increase in osteocyte lacunar area (Lac.Ar) compared to sham-operated animals. Furthermore, acetabular biopsies from patients with PO also showed significantly (p<0.001) increased osteocyte lacunar size in trabecular bone adjacent to PE particles, compared with osteocyte lacunar size in bone from primary THR patients. Together, these findings suggest a previously unrecognised action of UHMWPE wear particles on osteocytes, which directly results in a loss of osteocyte perilacunar bone. This action may exacerbate the indirect pro-osteoclastic action of UHMWPE-affected osteocytes, previously shown to contribute to aseptic loosening of orthopaedic implants. This study addresses the clinical problem of periprosthetic osteolysis, bone loss in response to polyethylene wear particles derived from materials used in orthopaedic implants. Periprosthetic osteolysis has been thought to be due largely to wear particles stimulating the activity of bone resorbing osteoclasts. However, in this study we demonstrate for the first time that polyethylene particles stimulate another type of bone loss, mediated by the direct activity of bone mineral embedded osteocytes, termed osteocytic osteolysis or osteocyte perilacunar remodelling. This study provides new mechanistic insight into wear-particle mediated bone loss and represents a new paradigm for the way in which bone cells, namely osteocytes, the key controlling cell type in bone, react to biomaterials.
Publisher: Oxford University Press (OUP)
Date: 20-06-2013
DOI: 10.1111/JPHP.12088
Abstract: Osteochondrin S, a natural product derived from connective tissues and yeast, is used to treat osteoarthritis. The aim of this study was to determine the effect of Osteochondrin S on human osteoclast activity in vitro. Osteoclasts were derived from human peripheral blood mononuclear cells stimulated with macrophage colony-stimulating factor and receptor activator of nuclear factor kappa B (RANK) ligand. Cells were treated with 23.5–587.2 ng/ml Osteochondrin S or 0.2–5 mg/ml of RNA components (synovia, placenta, intervertebral disc or cartilage). The effects on osteoclast formation and resorptive activity were assessed. Real-time polymerase chain reaction was conducted to assess the expression of key osteoclast genes. Osteochondrin S and the in idual RNA extracts resulted in a concentration-dependent inhibition of human osteoclast activity. Osteochondrin S did not affect RANK, nuclear factor of activated T cells (NFATc1), osteoclast-associated receptor or cathepsin K expression. However, there was a significant (P & 0.05) reduction in mRNA expression of calcitonin receptor. Osteochondrin S treatment also significantly increased the expression of osteoclast inhibitory factor interferon-β and, interestingly, increased the expression of tumour necrosis-α-like weak inducer of apoptosis (TWEAK). Osteochondrin S inhibited the resorptive ability of osteoclasts. These actions are likely to occur at a late stage during osteoclast formation, downstream of NFATc1. Overall, the findings show that Osteochondrin S inhibition of osteoclast activity may be responsible for its beneficial effects on diseases such as osteoarthritis.
Publisher: Wiley
Date: 02-06-2016
DOI: 10.1111/JRE.12290
Abstract: Histone deacetylase inhibitors (HDACi) are being considered to treat chronic inflammatory diseases at low doses. Currently HDACi that are more specific are being developed to target particular HDACs therefore, this study aimed to determine levels and distribution of class I and II HDAC in human gingival s les obtained from patients with chronic periodontitis. Gingival biopsies were obtained from patients with and without (mild inflammation, no bone loss) periodontitis. Total RNA was isolated for real-time quantitative polymerase chain reaction to determine expression of HDACs 1-10. Immunohistochemistry was used to determine protein distribution of HDACs 1, 5, 8 and 9. Factor VIII, CD3 and tartrate resistant acid phosphatase (TRAP) were detected in serial sections to identify blood vessels, lymphocytes, pre-osteoclasts and osteoclasts cells respectively. Tumour necrosis factor α (TNF-α) expression was also assessed. mRNA for HDAC 1, 5, 8 and 9 were significantly upregulated in chronic periodontitis gingival tissues compared to non-periodontitis s les (p < 0.05). Significantly higher HDAC 1 protein expression was observed in chronic periodontitis s les (p < 0.05), and was associated with CD3, TRAP and TNF-α-positive cells. HDAC 1, 5, 8 and 9 were expressed strongly by the factor VIII-positive microvasculature in the chronic periodontitis gingival tissues. HDAC 1, 5, 8 and 9 expression was higher in gingival tissues from patients with chronic periodontitis compared to non-periodontitis s les. Results suggest that these HDACs could therefore be targeted with specific acting HDACi.
Publisher: Springer Science and Business Media LLC
Date: 23-01-2013
DOI: 10.1007/S10787-012-0166-0
Abstract: Inhibition of histone deacetylases (HDAC) is emerging as a novel approach to treat a variety of diseases. Recently, broad acting inhibitors of HDAC have been shown to have anti-inflammatory effects both in vitro and in vivo. It is significant that these anti-inflammatory effects are observed at 10-100 fold lower concentrations than their anti-cancer effects. The broad action of these compounds makes it difficult to determine which HDAC enzymes are important in inflammation. Although showing promise it is unlikely that these drugs will progress to the clinic for treating inflammatory diseases due to number of HDACs they affect and the widespread activity of the enzymes throughout the body. Accordingly, research is now progressing to targeting specific HDAC enzymes to improve efficacy of treatment as well as reduce the risk of any unwanted side effects. Understanding the role specific HDACs play in inflammatory disease will help us to identify novel anti-inflammatory treatments. This manuscript is designed to review our limited knowledge in this field.
Publisher: OMICS Publishing Group
Date: 10-2009
DOI: 10.2217/IJR.09.42
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1016/J.BBRC.2012.09.077
Abstract: Osteoclasts are specialised bone resorptive cells responsible for both physiological and pathological bone loss. Osteoclast differentiation and activity is dependent upon receptor activator NF-kappa-B ligand (RANKL) interacting with its receptor RANK to induce the transcription factor, nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1). The immunoreceptor tyrosine-based activation motif (ITAM)-dependent pathway has been identified as a co-stimulatory pathway in osteoclasts. Osteoclast-associated receptor (OSCAR) and triggering receptor expressed in myeloid cells (TREM2) are essential receptors that pair with adaptor molecules Fc receptor common gamma chain (FcRγ) and DNAX-activating protein 12kDa (DAP12) respectively to induce calcium signalling. Treatment with calcineurin-NFAT inhibitors, Tacrolimus (FK506) and the 11R-VIVIT (VIVIT) peptide, reduces NFATc1 expression consistent with a reduction in osteoclast differentiation and activity. This study aimed to investigate the effects of inhibiting calcineurin-NFAT signalling on the expression of ITAM factors and late stage osteoclast genes including cathepsin K (CathK), Beta 3 integrin (β3) and Annexin VIII (AnnVIII). Human peripheral blood mononuclear cells (PBMCs) were differentiated with RANKL and macrophage-colony stimulating factor (M-CSF) over 10days in the presence or absence of FK506 or VIVIT. Osteoclast formation (as assessed by tartrate resistant acid phosphatase (TRAP)) and activity (assessed by dentine pit resorption) were significantly reduced with treatment. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis demonstrated that FK506 treatment significantly (p<0.05) reduced the expression of NFATc1, CathK, OSCAR, FcRγ, TREM2 and DAP12 during the terminal stage of osteoclast formation. VIVIT treatment significantly (p<0.05) decreased CathK, OSCAR, FcRγ, and AnnVIII, gene expression. This data suggest FK506 and VIVIT act differently in targeting the calcineurin-NFAT signalling cascade to suppress key mediators of the ITAM pathway during late stage osteoclast differentiation and this is associated with a reduction in both osteoclast differentiation and activity.
Publisher: Oxford University Press (OUP)
Date: 16-12-2011
DOI: 10.1111/J.2042-7158.2011.01421.X
Abstract: Despite progress in developing many new anti-inflammatory treatments in the last decade, there has been little progress in finding treatments for bone loss associated with inflammatory diseases, such as rheumatoid arthritis and periodontitis. For instance, treatment of rheumatic diseases with anti-tumour necrosis factor-alpha agents has been largely successful in reducing inflammation, but there have been varying reports regarding its effectiveness at inhibiting bone loss. In addition, there is often a delay in finding the appropriate anti-inflammatory therapy for in idual patients, and some therapies, such as disease modifying drugs, take time to have an effect. In order to protect the bone, adjunct therapies targeting bone resorption are being developed. This review focuses on new treatments based on using histone deacetylase inhibitors (HDACi) to suppress bone loss in these chronic inflammatory diseases. A number of selected HDACi have been shown to suppress bone resorption by osteoclasts in vitro and in animal models of chronic inflammatory diseases. Recent reports indicate that these small molecules, which can be administered orally, could protect the bone and might be used in combination with current anti-inflammatory treatments. HDACi do have potential to suppress bone destruction in chronic inflammatory diseases including periodontitis and rheumatoid arthritis.
Publisher: Oxford University Press (OUP)
Date: 31-03-2015
DOI: 10.1093/RHEUMATOLOGY/KEV022
Abstract: Histone deacetylase 1 (HDAC1) is highly expressed in the synovium of RA patients. Thus we aimed to investigate a novel HDAC inhibitor (HDACi), NW-21, designed to target HDAC1. The effect of NW-21 on osteoclast formation and activity, cytokine and chemokine expression in vitro and arthritis in mice was assessed. The effects on human osteoclast formation and activity derived from human blood monocytes stimulated with receptor activator of nuclear factor κB ligand (RANKL) and M-CSF were assessed. The anti-inflammatory activity of NW-21 was assessed using human monocytes stimulated with either TNF-α or lipopolysaccharide for 24 h. mRNA expression of monocyte chemotactic protein 1 (MCP-1), TNF-α, macrophage inflammatory protein 1α (MIP-1α), IL-1 and RANTES (regulated on activation, normal T cell expressed and secreted) was assessed. The effect of NW-21 in the collagen antibody-induced arthritis model was assessed following daily oral administration at 5 mg/kg/day. The HDAC1 inhibitors NW-21 and MS-275 were compared with a broad-acting HDACi, 1179.4b. Effects on inflammation and bone were assessed using paw inflammation scoring, histology and live animal micro-CT. NW-21 suppressed osteoclast formation and activity as well as significantly reducing mRNA expression of MCP-1 and MIP-1α in monocytes stimulated by lipopolysaccharide or TNF-α (P < 0.05) in vitro. Only inhibitors that targeted HDAC1 (NW-21 and MS-275) reduced inflammation and bone loss in the arthritis model. The results indicate that inhibitors targeting HDAC1, such as NW-21 and MS-275, may be useful for treating RA, as such drugs can simultaneously target both inflammation and bone resorption.
Publisher: Wiley
Date: 05-2010
Publisher: Wiley
Date: 20-01-2015
DOI: 10.1111/SJI.12259
Publisher: Wiley
Date: 15-12-2016
DOI: 10.1111/JRE.12339
Abstract: Periodontitis is the most common bone loss pathology in adults and if left untreated is responsible for premature tooth loss. Cytokines, such as tumour necrosis factor-α (TNFα), involved in the chronic inflammatory response within the periodontal gingiva, significantly influence the normal bone remodelling processes. In this review, the effects of TNFα on bone metabolism in periodontitis are evaluated in relation to its direct and indirect actions on bone cells including osteoclasts, osteoblasts and osteocytes. Evidence published to date suggests a potent catabolic role for TNFα through the stimulation of osteoclastic bone resorption as well as the suppression of osteoblastic bone formation and osteocytic survival. However, the extent and timing of TNFα exposure in vitro and in vivo greatly influences its effect on skeletal cells, with contradictory anabolic activity observed with TNFα in a number of studies. None the less, it is evident that managing the chronic inflammatory response in addition to the deregulated bone metabolism is required to improve periodontal and inflammatory bone loss treatments.
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.ACTBIO.2015.11.025
Abstract: Peri-prosthetic osteolysis (PPO) occurs in response to prosthetic wear particles causing an inflammatory reaction in the surrounding tissue that leads to subsequent bone loss. Semaphorin-3a (SEM3A), neuropilin-1 (NRP1) and plexin-A1 (PLEXA1) are axonal guidance molecules that have been recently implicated in regulating bone metabolism. This study investigated SEM3A, NRP1 and PLEXA1 protein and mRNA expression in human PPO tissue and polyethylene (PE) particle-stimulated human peripheral blood mononuclear cell (PBMC)-derived osteoclasts in vitro. In addition, the effects of tumour necrosis factor alpha (TNFα) on cultured osteoclasts was assessed. In PPO tissues, a granular staining pattern of SEM3A and NRP1 was observed within large multi-nucleated cells that contained prosthetic wear particles. Immunofluorescent staining confirmed the expression of SEM3A, NRP1 and PLEXA1 in large multi-nucleated human osteoclasts in vitro. Furthermore, SEM3A, NRP1 and PLEXA1 mRNA levels progressively increased throughout osteoclast differentiation induced by receptor activator of nuclear factor κB ligand (RANKL), and the presence of PE particles further increased mRNA expression of all three molecules. Soluble SEM3A was detected in human osteoclast culture supernatant at days 7 and 17 of culture, as assessed by ELISA. TNFα treatment for 72h markedly decreased the mRNA expression of SEM3A, NRP1 and PLEXA1 by human osteoclasts in vitro. Our findings suggest that SEM3A, NRP1 and PLEXA1 may have important roles in PPO, and their interactions, alone or as a complex, may have a role in pathological bone loss progression. Peri-prosthetic osteolysis occurs in response to prosthetic wear particles causing an inflammatory reaction in the surrounding tissue that leads to subsequent bone loss. The rate of hip and knee arthroplasty is increasing by at least 5% per year. However, these joint replacements have a finite lifespan, with data from the National Joint Replacement Registry (Australia) showing that the major cause of failure of total hip replacements is aseptic loosening. In aseptic loosening, wear particles liberated from prostheses are phagocytosed by macrophages, leading to release of inflammatory cytokines and up-regulation of osteoclast formation and activity. Semaphorin-3a, neuropilin-1 and plexin-A1 are axonal guidance molecules that have been recently implicated in regulating bone metabolism. This is the first report to show that these molecules may be involved in the implant failure.
Publisher: Public Library of Science (PLoS)
Date: 24-06-2014
Publisher: Hindawi Limited
Date: 2015
DOI: 10.1155/2015/564042
Abstract: Objective . To investigate the effect of Embelin, an inhibitor of X-Linked Inhibitor of Apoptosis Protein (XIAP), on inflammation and bone erosion in a collagen antibody induced arthritis (CAIA) in mice. Methods . Four groups of mice ( n = 6 per group) were allocated: CAIA untreated mice, CAIA treated with Prednisolone (10 mg/kg/day), CAIA treated with low dose Embelin (30 mg/kg/day), and CAIA treated with high dose Embelin (50 mg/kg/day). Joint inflammation was evaluated using clinical paw score and histological assessments. Bone erosion was assessed using micro-CT, tartrate resistant acid phosphatase (TRAP) staining, and serum carboxy-terminal collagen crosslinks (CTX-1) ELISA. Immunohistochemistry was used to detect XIAP protein. TUNEL was performed to identify apoptotic cells. Results . Low dose, but not high dose Embelin, suppressed inflammation as reflected by lower paw scores ( P 0.05 ) and lower histological scores for inflammation. Low dose Embelin reduced serum CTX-1 ( P 0.05 ) and demonstrated lower histological score and TRAP counting, and slightly higher bone volume as compared to CAIA untreated mice. XIAP expression was not reduced but TUNEL positive cells were more abundant in Embelin treated CAIA mice. Conclusion . Low dose Embelin suppressed inflammation and serum CTX-1 in CAIA mice, indicating a potential use for Embelin to treat pathological bone loss.
Publisher: Wiley
Date: 21-03-2011
Publisher: Wiley
Date: 27-04-2009
DOI: 10.1111/J.1600-0765.2008.01132.X
Abstract: Live-animal micro-computed tomography is a new and promising technique that can be used to quantify changes in bone volume for periodontal disease models. The major aim of this study was to develop the methodology of live-animal micro-computed tomography and to determine the effect of a novel secretory phospholipase A2 inhibitor on alveolar bone loss. Periodontitis was induced in mice by oral infection with Porphyromonas gingivalis over a period of 13 wk, and live-animal micro-computed tomography scans were taken at different time-points to determine bone volume changes with disease progression. This enabled conclusions to be made as to when treatment was most likely to be effective. In addition, the model was used to investigate a novel drug, the secretory phospholipase A2 inhibitor, KHO64, and its potential ability to inhibit osteoclast bone resorption and treat periodontitis. The results from live-animal micro-computed tomography scans revealed greater, statistically significant, bone volume loss in diseased mice compared with normal mice (p < 0.05). This corresponded to a larger area from the cemento-enamel junction to the alveolar bone crest, as assessed by stereo imaging (p < 0.001). These techniques can therefore detect and quantify alveolar bone loss. Both methods revealed that KHO64 had no significant effect on the volume of bone resorption. Live-animal micro-computed tomography is a robust, reproducible technique that clearly demonstrates significant time-dependent changes in alveolar bone volume in a small-animal model of periodontitis.
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.BONE.2016.11.028
Abstract: Histone deacetylases (HDACs)
Publisher: Wiley
Date: 28-01-2013
DOI: 10.1002/JCP.24259
Abstract: Azithromycin is an antibiotic with anti-inflammatory properties used as an adjunct to treat periodontitis, a common inflammatory mediated condition featuring pathologic alveolar bone resorption. This study aimed to determine the effect of azithromycin on human osteoclast formation and resorptive activity in vitro. Osteoclasts were generated from peripheral blood mononuclear cells stimulated with macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor kappa B (RANK) ligand. The effects of azithromycin at concentrations ranging from 0.5 to 40 µg/ml were tested. Osteoclast formation and activity, acidification, actin ring formation and expression of mRNA, and protein encoding for key osteoclast genes were assessed. The results demonstrated that azithromycin reduced osteoclast resorptive activity at all concentrations tested with osteoclast formation being significantly reduced at the higher concentrations (20 and 40 µg/ml). mRNA and protein expression of key osteoclast transcription factor Nuclear Factor of Activated T cells (NFATc1) was significantly reduced by azithromycin at later stages of osteoclast development (day 17). Azithromycin also reduced tumor necrosis factor receptor associated factor-6 (TRAF6) mRNA expression at day 14, and cathepsin K mRNA expression at days 14 and 17. Integrin β3 and MMP-9 mRNA expression was reduced by azithromycin at day 17 in osteoclasts cultured on dentine. The osteoclast proton pump did not appear to be affected by azithromycin, however formation of the actin ring cytoskeleton was inhibited. This study demonstrates that azithromycin inhibits human osteoclast function in vitro, which may account for at least some of the beneficial clinical effects observed with azithromycin treatment in periodontitis.
Publisher: Springer Science and Business Media LLC
Date: 04-05-2013
DOI: 10.1007/S10787-013-0171-Y
Abstract: Chondroitin sulfate (CS) compounds are commonly used to manage OA symptoms. Recent literature has indicated that abnormal subchondral bone metabolism may have a role in the pathogenesis of OA. The aim of this study was to access the effects of chondroitin sulfate obtained from bovine, fish and porcine sources on human osteoclast formation and activity in vitro. Human osteoclasts were generated from blood mononuclear cells. Cells were cultured over 17 days with the addition of macrophage colony stimulating factor (M-CSF) and then stimulated with receptor activator of nuclear factor kappa B ligand from day 7. Cells were treated with the CS commencing from day 7 onwards. To assess effects on osteoclasts, tartrate resistant acid phosphatate (TRAP) expression and resorption of whale dentine assays were used. Bovine-derived CS consistently suppressed osteoclast activity at concentrations as low as 1 μg/ml. Fish and porcine CS was less consistent in their effects varying with different donor cells. All CS compounds had little effect on TRAP activity. mRNA analysis using real-time PCR of bovine CS treated cells indicated that the inhibition of activity was not due to inhibition of the late stage NFATc1 transcription factor (p > 0.05). These results are consistent with CS inhibition of mature osteoclast activity rather than the formation of mature osteoclasts. It would appear that there are differences in activity of the different CS compounds with bovine-derived CS being the most consistently effective inhibitor of osteoclast resorption, but the results need to be confirmed.
No related grants have been discovered for Melissa Cantley.