ORCID Profile
0000-0002-5422-3758
Current Organisation
University of Adelaide
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Elsevier BV
Date: 06-2000
DOI: 10.1016/S8756-3282(00)00280-5
Abstract: An in vitro culture system to generate human osteoclasts (OC) was recently described in which OC precursors in the human peripheral blood mononuclear cell (PBMC) population differentiate in the presence of murine ST-2 stromal cells. We used this culture system to define the cytokine environment in which human OC form and to determine the separate contributions of the stromal and hematopoietic elements. We designed a panel of reverse transcriptase-polymerase chain reaction (RT-PCR) primers that specifically lify the respective murine or human mRNA species that correspond to cytokines and their cognate receptors previously shown to promote or inhibit OC differentiation. ST-2 cells were cocultured with human PBMC for up to 21 days in the presence of 1alpha,25(OH)(2) vitamin D(3), dexamethasone, and recombinant human macrophage-colony stimulating factor (M-CSF). OC formation was monitored by the appearance of cells that were positive for tartrate-resistant acid phosphatase (TRAP) and able to form resorption lacunae on slices of dentine. We found that the ST-2 cells in these cultures express messenger RNA (mRNA) encoding a repertoire of many of the reported osteoclastogenic factors (interleukins [IL]-1/IL-1R1, IL-11, IL-6/IL-6R, and IL-17 transforming growth factor [TGF]-beta), as well as the recently described OC differentiation factor (ODF/TRANCE/RANKL). The stromal cells also expressed mRNA encoding two molecules shown to be inhibitory to osteoclastogenesis, osteoprotegerin (OPG) and IL-18. OPG, IL-1, IL-1R1, IL-6, IL-6R, IL-11R, IL-17, IL-18, IL-18R, TGF-beta, and M-CSF were expressed by both the stromal cells and the PBMC. Expression of mRNA encoding RANK, IL-1R2, and c-fms, was specific for the PBMC. In addition, PBMC were found to express sIL-6R, granulocyte macrophage (GM)-CSF, GM-CSFRalpha, and tumor necrosis factor (TNF)-alpha. Whereas this indicated that human OC formation occurs in a complex environment of many positive and negative influences, we identified three apparent features of the cytokine environment that may be a characteristic of normal osteoclast formation. First, the ratio of mouse ODF:OPG mRNA was found to increase during the cocultures, consistent with a key role for ODF in the promotion by stromal cells of OC formation. Second, we found that mRNA encoding IL-1 and IL-17, as well as IL-6 and sIL-6R, were coordinately expressed by the PBMC. Third, analysis of the culture medium showed that the PBMC secreted IL-1, IL-6, and TNF-alpha protein only in coculture with ST-2 cells during the first few days of osteoclast development. We conclude that human OC formation occurs in a complex environment of many positive and negative influences however, these are likely to be strictly regulated by a coordinated cytokine response of both stromal and hematopoietic cells.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-10-2021
Publisher: Springer Science and Business Media LLC
Date: 2006
DOI: 10.1186/AR1938
Publisher: Elsevier BV
Date: 11-2007
DOI: 10.1016/J.BBAEXP.2007.08.005
Abstract: The calcitonin receptor (CTR) is expressed in a wide variety of tissues and cell types. In bone, its expression is restricted to osteoclasts, the cells that mediate bone resorption. The human CTR (hCTR) gene has a complex structural organization that exhibits similarity to the porcine (pCTR) and mouse (mCTR) CTR genes. In these species, alternative splicing of a single gene generates multiple CTR isoforms that are distributed in both tissue-specific and species-specific patterns. However, the structural organization of the 5' putative regulatory region and transcriptional mechanisms responsible for tissue-specific expression of the different CTR isoforms are not fully defined. The present studies were undertaken to characterize the structural organization of the 5'-region of the hCTR and identify the regulatory regions involved in osteoclast-specific transcriptional activation. Analysis of mRNA prepared from human osteoclasts using reverse transcription-polymerase chain reaction (RT-PCR) and transient transfection of hCTR promoter-luciferase reporter constructs identified two regions in the 5'-flanking sequence of the hCTR gene that regulated CTR gene expression in osteoclasts. Both of these putative promoters were responsive to the osteoclast-inducing cytokine, receptor activator of NF-kappaB ligand (RANKL) and demonstrated trans-activation by the RANKL-induced transcription factor nuclear factor of activated T cells (NFATc1), consistent with a role in regulating CTR gene expression in osteoclasts.
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: Research Square Platform LLC
Date: 09-10-2020
DOI: 10.21203/RS.3.RS-88109/V1
Abstract: Background : Juvenile Idiopathic Arthritis (JIA) is a chronic rheumatic disease that shows variation in subtype distribution by geographic regions. The aim of this study was to create a JIA registry, which could describe the epidemiology and characteristics of JIA patients in South Australia (SA). Methods : Prospectively collected data from JIA patients at the Women’s and Children’s Hospital in Adelaide, between August 2019 and March 2020 were reported. All children and young people diagnosed with JIA according to the International League of Associations for Rheumatology (ILAR) classification criteria were eligible for inclusion. Data including demographics, complications/comorbidities, medications, disease activity as well as patient-reported data using Childhood Health Assessment Questionnaire (CHAQ) were documented. Non-identified data were extracted from this registry and utilised in descriptive analysis and comparative studies. Results : There are currently n =112 JIA patients in this registry, including n =11 incident cases (9.8%), with a predominance of female ( n =75, 67.0%). The median disease duration was 3.6 years (interquartile range 1.3-7.6). The most common subtype was persistent oligoarthritis ( n =35/112, 31.3%), followed by rheumatoid factor-negative polyarthritis ( n =32/112, 28.6%), extended oligoarthritis ( n =23/112, 20.5%), enthesitis-related arthritis (ERA n =12/112, 10.7%), systemic onset arthritis ( n =5/112, 4.5%), rheumatoid factor-positive polyarthritis ( n =3/112, 2.7%) and psoriatic arthritis ( n =2/112, 1.8%). Complications were documented in n =40/112 (35.7%) patients, with n =21/94 (22.3%) observed to have uveitis, and musculoskeletal complications observed in n =10/112 (8.9%). Methotrexate intolerance was present in n =10/79 (12.7%) patients. Forty-nine out of 112 (43.8%) patients had at least one comorbidity, with anxiety/depression ( n =5/112, 4.5%) and asthma ( n =5/112, 4.5%) being the most common. Around half of patients ( n =52/112, 46.4%) had clinically inactive disease at enrolment and most ( n =85/112, 75.9%) reported no to low functional disability. Non-steroidal anti-inflammatory drugs have been almost universally used ( n =100/112, 89.3%), and n =26/112 (23.2%) have received treatment with biologics. Conclusions : In this JIA registry study, we found that the JIA cohort in SA is female-dominated with persistent oligoarthritis as the most common subtype, consistent with other studies. Most patients have good disease control and report no or mild disability. Further longitudinal work will add to the current description of our JIA cohort and assist improvement of clinical care.
Publisher: Oxford University Press (OUP)
Date: 06-2001
DOI: 10.1093/RHEUMATOLOGY/40.6.623
Abstract: This study investigated the involvement of the recently identified regulators of osteoclast formation RANKL [receptor activator of nuclear factor kappaB (RANK) ligand, osteoclast differentiation factor, TRANCE, osteoprotegerin ligand] and its natural inhibitor, osteoprotegerin (OPG), in the bone erosion of rheumatoid arthritis (RA). mRNA was extracted from cells isolated from the pannus and synovial membrane regions of joints of 11 RA patients. Semiquantitative reverse transcription-polymerase chain reaction was carried out, and the isolated cells were also cultured to determine their ability to form osteoclasts. mRNAs encoding RANKL, RANK, OPG and macrophage-colony stimulating factor were expressed by cells isolated from RA joints. In addition, mRNA encoding for tumour necrosis factor apoptosis-inducing ligand and the osteoclast markers tartrate-resistant acid phosphatase and calcitonin receptor were also often expressed. Osteoclasts capable of forming resorption lacunae were generated from cells in the RA joints. At 50 ng/ml, recombinant OPG completely inhibited the resorptive activity of these cells. There was a significant correlation between the ratio of RANKL mRNA to OPG mRNA and the number of resorption pits produced (P = 0.028). These data suggest that RANKL is an essential factor for osteoclast formation by cells in the rheumatic joint and that OPG may prevent the bone erosion seen in RA joints.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-1999
DOI: 10.1097/00007632-199903150-00003
Abstract: Facet joints from sheep lumbar spines were examined for histologic evidence of osteoarthrosis after anular incision. To describe the sequence of changes in facet joints in an animal model of disc degeneration. There are many studies with results showing a link between facet joint osteoarthrosis and disc degeneration, but the development of osteoarthrosis in facet joints has not been observed in a controlled study of disc degeneration. Histologic features of facet joint degeneration were compared with established descriptions of human osteoarthrosis, and the sequence of changes was documented in a controlled prospective study of disc degeneration. Osteoarthrosis in sheep lumbar facet joints is similar to that described in human joints and develops in response to anular injury. Discs degenerate relatively soon after anular incision, but there is a long delay in the appearance of significant changes to the facet joints at the level of anular incision and adjacent levels. The results shows that facet joints in sheep undergo osteoarthrotic changes in response to disc degeneration and confirm the sheep as a suitable model for the study of degenerative spinal disorders.
Publisher: Springer Science and Business Media LLC
Date: 23-12-2014
DOI: 10.1038/SREP07595
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: BMJ
Date: 07-12-2009
Abstract: Analysis of tissues retrieved from the bone-pannus interface from patients with rheumatoid arthritis (RA) and studies in animal models of inflammatory arthritis provide strong evidence that osteoclasts, the cells that are essential for physiological bone resorption, are responsible for articular bone destruction in RA. However, current treatments that specifically target osteoclast-mediated bone resorption in RA have not been successful in preventing bone erosions, and new therapeutic strategies are needed. It has been noted that, although osteoclast precursors are present within the bone microenvironment at sites of pathological bone resorption, cells expressing the full morphological and functional properties of mature osteoclasts are restricted to the immediate bone surface and adjacent calcified cartilage. These findings provide evidence that, in addition to requirements for specific cytokines, interaction of osteoclast precursors with these mineralised matrices results in activation of specific signal pathways and the induction of unique gene products that are essential for terminal osteoclast differentiation and activation. These studies are designed to define the gene products and signalling pathways regulated by bone and calcified cartilage, to identify new molecular targets and novel therapeutic approaches for preventing osteoclast-mediated joint destruction in RA and related forms of pathological bone loss.
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: Springer Science and Business Media LLC
Date: 30-05-2017
DOI: 10.1007/S10753-017-0597-2
Abstract: Osteoclast-associated receptor (OSCAR) is a co-stimulatory receptor in osteoclastogenesis. Synovial tissues from active rheumatoid arthritis (RA) patients express higher levels of OSCAR compared with osteoarthritic and normal patients however, the comparison of OSCAR levels in different regions of active RA synovium has not been reported. The regulation of OSCAR by TNF-α and receptor activator of NF kappa β ligand (RANKL) in pre-osteoclasts/osteoclasts in vitro is unclear. OSCAR and tartrate-resistant acid phosphatase (TRAP) expression levels did not differ between the cartilage pannus junction (CPJ) and non-CPJ regions in active RA. We demonstrate a similar pattern of OSCAR expression in the CPJ and non-CPJ synovial tissue from patients with active RA. OSCAR was associated with mononuclear cells in both the lining and sub-lining and endothelial cells (von Willebrand factor positive). Pre-osteoclasts (TRAP-positive cells) were present in the lining and sub-lining of both regions. OSCAR messenger RNA (mRNA) expression and release by pre-oscteoclasts/osteoclasts was modulated by RANKL with/without TNF-α in vitro. Osteoclast resorption on dentine slices was significantly greater with TNF-α pre-treatment and RANKL (10 ng/ml) than RANKL 10 or 50 ng/ml alone or RANKL 10 ng/ml with TNF-α given from day 3 post-RANKL. The lower levels of OSCAR mRNA expression corresponded with high osteoclast activity levels.
Publisher: Wiley
Date: 20-02-2008
DOI: 10.1002/JCP.21344
Abstract: Expression of the alpha(v)beta(3) integrin is required for normal osteoclast function. We previously showed that an evolutionary conserved NFATc1 binding site is required for RANKL induction and NFATc1 transactivation of the human beta(3) promoter. The mechanism conferring specificity for RANKL induction and NFATc1 transduction of the beta(3) gene in osteoclast differentiation is unclear since NFATc1 is expressed and activated in numerous cell types that do not express the beta(3) gene. PU.1 is an ETS family transcription factor in myeloid cells associated with expression of various osteoclast genes. The present study investigates the role of NFATc1 in concert with PU.1 in osteoclast-specific transcription of the mouse beta(3) integrin gene. The mouse beta(3) promoter was transactivated by NFATc1 in RAW264.7 cells and deletion or mutation of either of the conserved NFAT and PU.1 binding sites abrogated transactivation. NFATc1 transactivation of the mouse beta(3) promoter was specifically dependent on co-transfected PU.1 in HEK293 cells, to the exclusion of other ETS family members. Direct binding of NFATc1 and PU.1 to their cognate sequences was demonstrated by EMSA and NFATc1 and PU.1 occupy their cognate sites in RANKL-treated mouse marrow precursors in chromatin immuno-precipitation (ChIP) assays. TAT-mediated transduction with dominant-negative NFATc1 dose-dependently blocked endogenous expression of the mouse beta(3) integrin and the formation of TRAP positive multinucleated cells in RANKL-treated mouse macrophages. These data provide evidence that NFATc1, in concert with PU.1, are involved in regulation of beta(3) integrin expression during osteoclast differentiation and suggest that PU.1 confers specificity to the NFATc1 response to macrophage lineage cells.
Publisher: Wiley
Date: 22-11-2005
DOI: 10.1111/J.0105-2896.2005.00338.X
Abstract: Rheumatoid arthritis, juvenile idiopathic arthritis, the seronegative spondyloarthropathies including psoriatic arthritis, and systemic lupus erythematosus are all ex les of rheumatic diseases in which inflammation is associated with skeletal pathology. Although some of the mechanisms of skeletal remodeling are shared among these diseases, each disease has a unique impact on articular bone or on the axial or appendicular skeleton. Studies in human disease and in animal models of arthritis have identified the osteoclast as the predominant cell type mediating bone loss in arthritis. Many of the cytokines and growth factors implicated in the inflammatory processes in rheumatic diseases have also been demonstrated to impact osteoclast differentiation and function either directly, by acting on cells of the osteoclast-lineage, or indirectly, by acting on other cell types to modulate expression of the key osteoclastogenic factor receptor activator of nuclear factor (NF) kappaB ligand (RANKL) and/or its inhibitor osteoprotegerin (OPG). Further elucidation of the mechanisms responsible for inflammation-induced bone loss will potentially lead to the identification of novel therapeutic strategies for the prevention of bone loss in these diseases. In this review, we provide an overview of the cell types, inflammatory mediators, and mechanisms that are implicated in bone loss and new bone formation in inflammatory joint diseases.
Publisher: BMJ
Date: 12-2002
Abstract: To compare receptor activator of NF-kappaB ligand (RANKL) production in the synovial tissue from patients with active rheumatoid arthritis (RA), inactive RA, spondyloarthropathies (SpA), osteoarthritis, and from normal subjects. In addition, to establish the cell lineages expressing RANKL in these tissues. Immunohistological analysis of frozen synovial tissue biopsy specimens was performed using a monoclonal antibody (mAb) to detect RANKL. Sections were evaluated by computer assisted image analysis and semiquantitative analysis to compare RANKL expression between groups. Dual and sequential labelling with mAb RANKL and cell lineage specific monoclonal antibodies were used to determine the types of cells expressing RANKL. Higher levels of RANKL were expressed in tissues from patients with active RA and SpA than in tissues from patients with inactive RA, osteoarthritis, and from normal subjects. RANKL protein was associated with CD3 antigen-positive lymphocytes and some macrophages. RANKL was predominantly associated with activated, memory T cells (CD45Ro positive cells) in patients with active RA and spondyloarthropathy (SpA). The highest levels of RANKL were detected in patients with RA with active synovitis and in some patients with SpA. An increase in RANKL in the inflamed joint of patients with RA, produced by infiltrating activated T cells and macrophages, is likely to be an important cause of joint erosions in RA.
Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1016/J.ACTBIO.2012.04.037
Abstract: Wear particle-induced orthopaedic prosthesis loosening is associated with elevated osteoclast activity. The immunoreceptor tyrosine-based activation motif (ITAM)-related molecules OSCAR, FcRγ, TREM2 and DAP12 are important for osteoclast formation. The aim of this study was to determine if these molecules are involved in peri-implant loosening by investigating their expression in peri-implant tissues obtained at revision of joint replacement components containing polyethylene (PE) wear particles, and in osteoclasts formed in vitro in the presence of PE particles. The results showed that there was a marked and statistically significant increase in protein levels of the ITAM-related molecules in the revision tissues. The levels of OSCAR, FcRγ, TREM2 and DAP12 mRNA in the revision tissues were also increased. In vitro PE particles stimulated osteoclast resorption in the presence of 50 ng ml(-1) receptor activator NFκB (RANKL) and significantly elevated the expression of OSCAR, FcRγ, TREM2 and DAP12 during osteoclast formation. These findings suggest that the ITAM signalling molecules and their co-receptors have a role in pathogenic bone loss associated with implant PE wear.
Publisher: Wiley
Date: 26-06-2003
DOI: 10.1034/J.1600-0765.2003.00615.X
Abstract: This study investigated the expression of key mediators that regulate differentiation of osteoclasts, receptor activator of nuclear factor kappaB ligand (RANKL), and its natural inhibitor, osteoprotegerin (OPG), in periodontitis. We aimed to compare the levels of the RANKL and OPG in the granulomatous tissue adjacent to areas of alveolar bone loss from patients with periodontitis to that present in tissue from patients without periodontitis. In addition, we aimed to determine the types of cells expressing these factors in these tissues and to demonstrate the expression of the osteoclastic markers, RANK and tartrate-resistant acid phosphatase (TRAP), in periodontitis. Frozen biopsy specimens were analysed using specific monoclonal antibodies and were evaluated by semiquantitative analysis and digital image analysis to compare levels of RANKL and OPG protein expression. Double labelling of frozen sections with antibodies to different cell lineage specific markers was used to determine the types of cells expressing these proteins. In situ hybridization was used to detect cells expressing RANK mRNA. Semiquantitative image analysis demonstrated that significantly higher levels of RANKL protein (P < 0.05) were expressed in the periodontitis tissue. Conversely, OPG protein was significantly lower (P < 0.05) in the periodontitis tissues. RANKL protein was associated with lymphocytes and macrophages. OPG protein was associated with endothelial cells in both tissues. Many leukocytes expressing RANK mRNA and TRAP were observed in periodontitis tissues. The change in the levels of these key regulators of osteoclast differentiation may play a major role in the bone loss seen in periodontitis.
Publisher: SAGE Publications
Date: 22-07-2021
DOI: 10.1369/00221554211033562
Abstract: Induction of severe inflammatory arthritis in the collagen antibody-induced arthritis (CAIA) murine model causes extensive joint damage and pain-like behavior compromising analysis. While mild models are less severe, their reduced, variable penetrance makes assessment of treatment efficacy difficult. This study aimed to compare macroscopic and microscopic changes in the paws, along with central nervous system activation between a mild and moderate CAIA model. Balb/c mice ( n=18) were allocated to control, mild, and moderate CAIA groups. Paw inflammation, bone volume (BV), and paw volume (PV) were assessed. Histologically, the front paws were assessed for joint inflammation, cartilage damage, and pre/osteoclast-like cells and the lumbar spinal cord and the periaqueductal gray (PAG) region of the brain for glial reactivity. A moderate CAIA dose induced (1) significantly greater local paw inflammation, inflammatory cell infiltration, and PV (2) significantly more osteoclast-like cells on the bone surface and within the surrounding soft tissue and (3) significantly greater glial reactivity within the PAG compared with the mild CAIA model. These findings support the use of a moderate CAIA model (higher dose of monoclonal antibodies with low-dose lipopolysaccharide) to induce more consistent histopathological features, without excessive joint destruction.
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: 24-03-2011
DOI: 10.1186/AR3294
Publisher: Wiley
Date: 23-09-2011
DOI: 10.1002/JCP.22699
Abstract: While attachment to bone is required for optimal osteoclast function, the molecular events that underlie this fact are unclear, other than that the cell requires adhesion to mineralized matrix to assume a fully differentiated phenotype. To address this issue, we cultured murine bone marrow-derived osteoclasts on either cell culture plastic or devitalized mouse calvariae to identify the distinct genetic profile induced by interaction with bone. Among a number of genes previously unknown to be expressed in osteoclasts we found that Annexin A8 (AnxA8) mRNA was markedly up-regulated by bone. AnxA8 protein was present at high levels in osteoclasts present in human tissues recovered from sites of pathological bone loss. The presence of bone mineral was required for up-regulation of AnxA8 mRNA since osteoclasts plated on decalcified bone express AnxA8 at low levels as did osteoclasts plated on native or denatured type I collagen. Finally, AnxA8-regulated cytoskeletal reorganization in osteoclasts generated on a mineralized matrix. Thus, we used a novel approach to define a distinct bone-dependent genetic program associated with terminal osteoclast differentiation and identified Anxa8 as a gene strongly induced late in osteoclast differentiation and a protein that regulates formation of the cell's characteristic actin ring.
Publisher: Springer Science and Business Media LLC
Date: 2012
DOI: 10.1186/AR4088
Publisher: Hindawi Limited
Date: 2015
DOI: 10.1155/2015/281287
Abstract: The field of osteoimmunology has emerged in response to the range of evidences demonstrating the close interrelationship between the immune system and bone metabolism. This is pertinent to immune-mediated diseases, such as rheumatoid arthritis and periodontal disease, where there are chronic inflammation and local bone erosion. Periprosthetic osteolysis is another ex le of chronic inflammation with associated osteolysis. This may also involve immune mediation when occurring in a patient with rheumatoid arthritis (RA). Similarities in the regulation and mechanisms of bone loss are likely to be related to the inflammatory cytokines expressed in these diseases. This review highlights the role of immune-related factors influencing bone loss particularly in diseases of chronic inflammation where there is associated localized bone loss. The importance of the balance of the RANKL-RANK-OPG axis is discussed as well as the more recently appreciated role that receptors and adaptor proteins involved in the immunoreceptor tyrosine-based activation motif (ITAM) signaling pathway play. Although animal models are briefly discussed, the focus of this review is on the expression of ITAM associated molecules in relation to inflammation induced localized bone loss in RA, chronic periodontitis, and periprosthetic osteolysis, with an emphasis on the soluble and membrane bound factor osteoclast-associated receptor (OSCAR).
Publisher: Springer Science and Business Media LLC
Date: 12-2003
DOI: 10.1163/156856003322699500
Abstract: Focal bone erosion is a major pathological feature of several common inflammatory diseases. Over the past decade there have been major advances in our understanding of the factors that regulate osteoclast formation and activity. It is now apparent that receptor activator for NFkappaB (RANK), its ligand RANKL (also known as TRANCE, osteoclast differentiation factor and osteoprotegerin (OPG) ligand) and the RANKL inhibitor OPG, are the major factors regulating osteoclast formation. These molecules influence normal bone physiology and now there is growing evidence that RANK-RANKL interactions also regulate osteoclast formation in disease. This paper reviews recent findings showing expression of RANK, RANKL and OPG in inflammatory diseases including rheumatoid arthritis, periodontal disease and peri-implant loosening. It is emerging that OPG and RANKL are key molecules regulating bone loss in disease and therapeutic intervention that targets these molecules may be helpful in treating a wide range of diseases.
Publisher: Springer US
Date: 2007
DOI: 10.1007/978-0-387-72009-8_14
Abstract: Osteoclast and their mononuclear cell precursors are present within the bone microenvironment at sites of physiologic and pathologic bone resorption. Analysis of tissues from sites of bone resorption reveal that cells expressing the full morphological and functional properties of mature osteoclasts are restricted to the immediate bone surface. We hypothesize that in addition to cytokines, components of the bone matrix and specific cell surface receptors on osteoclasts and their precursors play an essential role in determining the genetic profile and functional properties of fully differentiated resorbing osteoclasts. We have employed expression profiling, with an in vitro model of matrix-dependent osteoclast differentiation, to identify the molecular pathways by which bone matrix-interactions induce terminal osteoclast differentiation and activation. In preliminary studies, we have identified unique genes and transcriptional pathways that are induced by interaction of osteoclast precursors with specific components of the mineralized bone matrix. The authenticity of the gene profiles, as markers of osteoclast differentiation and activation, have been provisionally validated using an in vivo animal bone implantation model and by examination of tissues from patients with specific forms of pathologic osteoclast-mediated bone resorption. The ultimate goal of our studies is to identify new molecular targets for inhibiting osteoclast-mediated bone loss in disorders of pathologic bone loss. The early work of Walker et al. (Walker 1972) in parabiotic animals, and the subsequent studies of Burger et al. (Burger, Van der Meer, van de Gevel, et al. 1982) using a co-culture model with fetal bone rudiments and bone marrow-derived cells, have helped to establish that osteoclasts are derived from macrophage precursors of colony forming unit-macrophage (CFU-M lineage). As such, they share a common hematopoietic origin with other CFU-M lineage cells, including tissue macrophages that populate the lung (alveolar macrophages), liver (Kupfer cells), synovium (synovial macrophages) and other organs. They also share a common lineage
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.ACTBIO.2019.01.047
Abstract: Periprosthetic osteolysis is a major cause of implant failure in total hip replacements. Aseptic loosening caused by osteolytic lesions is associated with the production of bioactive wear particles from the articulations of implants. Wear particles infiltrate the surrounding tissue of implants, promoting inflammation as well as bone resorption. Osteocytes have been shown to both regulate physiological osteoclastogenesis and directly remodel their perilacunar bone matrix by the process of osteocytic osteolysis. We hypothesise that osteocytes respond to wear debris of orthopaedic implant materials by adopting a pro-catabolic phenotype and thus contribute to periprosthetic osteolysis through the known pathways of bone loss. Osteocyte responses to particles derived from clinically relevant materials, ultra-high molecular weight polyethylene (UHMWPE), highly cross-linked polyethylene (XLPE) and metal alloys, Ti6Al4V and CoCrMo, were examined in vitro in human primary osteocyte-like cultures. Osteocyte-like cells exposed to both polyethylene and metal wear particle types showed upregulated expression of catabolic markers associated with osteocytic osteolysis, MMP13, carbonic anhydrase 2 (CA2) and cathepsin K (CTSK). In addition, pro-osteoclastogenesis markers RANKL and M-CSF were induced, as well as the expression of pro-inflammatory cytokines, IL-6 and TNFα, albeit with different kinetics. These findings suggest a previously unrecognised action of wear particles of multiple orthopaedic materials on osteocytes, and suggest a multifaceted role for osteocytes in periprosthetic osteolysis. STATEMENT OF SIGNIFICANCE: This study addresses periprosthetic osteolysis, a major clinical problem leading to aseptic loosening of orthopaedic implants. It is well accepted that wear particles of polyethylene and of other implant materials stimulate the activity of bone resorbing osteoclasts. Our recent work provided evidence that commercial particles of ultra-high molecular weight polyethylene (UHMWPE) stimulated osteocytes to adopt a bone catabolic state. In this study we demonstrate for the first time that particles derived from materials in clinical use, conventional UHMWPE, highly cross-linked polyethylene (XLPE), and Ti6Al4V and CoCrMo metal alloys, all stimulate human osteocyte activities of osteocyte-regulated osteoclastogenesis, osteocytic osteolysis, proinflammatory responses, osteocyte apoptosis, albeit to varying extents. This study provides further mechanistic insight into orthopaedic wear particle mediated bone disease in terms of the osteocyte, the most abundant and key controlling cell type in bone.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-01-2020
Publisher: Springer Science and Business Media LLC
Date: 2006
DOI: 10.1290/0510075.1
Publisher: BMJ
Date: 19-12-2012
DOI: 10.1136/ANNRHEUMDIS-2012-202199
Abstract: The inflammatory arthropathies that include rheumatoid arthritis, the seronegative spondyloarthropathies and systemic lupus erythematosus are characterised by marked alterations in the architecture and structural integrity of peri-articular bone however, the pattern and natural history of the skeletal changes differs in these conditions. In part, this can be attributed to differences in the primary anatomical site of the inflammation, but also there is evidence that there are differences in the biological properties and products produced by inflammatory tissues. This review will focus on recent advances in the understanding of the cellular and molecular mechanisms that contribute to the differential pattern of articular bone remodelling in these prototypical inflammatory forms of arthritis.
Publisher: Hindawi Limited
Date: 04-03-2020
DOI: 10.1155/2020/6245798
Abstract: Rheumatoid arthritis is characterised by a chronic inflammatory response resulting in destruction of the joint and significant pain. Although a range of treatments are available to control disease activity in RA, bone destruction and joint pain exist despite suppression of inflammation. This study is aimed at assessing the effects of parthenolide (PAR) on paw inflammation, bone destruction, and pain-like behaviour in a mild collagen antibody-induced arthritis (CAIA) mouse model. CAIA was induced in BALB/c mice and treated daily with 1 mg/kg or 4 mg/kg PAR. Clinical paw inflammation was scored daily, and mechanical hypersensitivity was assessed on alternate days. At end point, bone volume and swelling in the paws were assessed using micro-CT. Paw tissue sections were assessed for inflammation and pre-/osteoclast-like cells. The lumbar spinal cord and the periaqueductal grey (PAG) and rostral ventromedulla (RVM) regions of the brain were stained for glial fibrillary acidic protein (GFAP) and ionised calcium-binding adaptor molecule 1 (IBA1) to assess for glial reactivity. Paw scores increased in CAIA mice from days 5-10 and were reduced with 1 mg/kg and 4 mg/kg PAR on days 8-10. Osteoclast-like cells on the bone surface of the radiocarpal joint and within the soft tissue of the hind paw were significantly lower following PAR treatment ( p 0.005 ). GFAP- and IBA1-positive cells in the PAG and RVM were significantly lower following treatment with 1 mg/kg ( p 0.0001 and p = 0.0004 , respectively) and 4 mg/kg PAR ( p 0.0001 and p = 0.001 , respectively). In the lumbar spinal cord, IBA1-positive cells were significantly lower in CAIA mice treated with 4 mg/kg PAR ( p = 0.001 ). The findings indicate a suppressive effect of both low- and moderate-dose PAR on paw inflammation, osteoclast presence, and glial cell reactivity in a mild CAIA mouse model.
Publisher: Elsevier BV
Date: 2003
DOI: 10.1016/S0142-9612(02)00324-1
Abstract: Loss of bone near joint prostheses is thought to be caused by activation of recruited osteoclasts by osteolytic mediators induced by wear particles. It is proposed that particles inhibit osteogenesis during bone remodelling causing a reduction in the levels of peri-implant bone. This study explores whether prosthetic particles modulate bone formation by affecting osteoblastic bone-related mRNAs (alkaline phosphatase, pro-collagen Ialpha1, osteopontin, osteonectin, osteocalcin, bone sialoprotein and thrombospondin) or their translated proteins using titanium alloy, commercially pure titanium, and cobalt-chrome particles. The direct effect of the particles revealed no change to the expression of the bone-related mRNAs in human bone-derived cells (HBDC) at the time points investigated although non-collagenous translated proteins expressed by these HBDC were significantly effected (p<0.05). Different patterns of expression for bone-related proteins were induced by the different particles both directly and indirectly. Inflammatory mediators (interleukin-1beta, tumor necrosis factor alpha, interleukin-6, and prostaglandin E2) had similar effects on HBDC to the media obtained from monocytes incubated with particles. This study shows that prosthetic wear particles can significantly modify the expression of bone-related proteins by osteogenic cells in vitro. These alterations in osteogenic activity at the interface of the implant and bone may be an important factor in the failure of many orthopaedic implants.
Publisher: Wiley
Date: 02-2000
DOI: 10.1002/(SICI)1097-4636(200002)49:2<167::AID-JBM3>3.0.CO;2-9
Abstract: The biological response to prosthetic wear particles is thought to stimulate the bone loss that often leads to prosthetic joint failure. This in vitro study investigates how metal particles corrode under physiological conditions and how biological responses to particles may change as particles age. Cobalt chrome alloy (CoCr) and 316L stainless steel (SS) particles of a similar size, shape, and concentration to those found in revision tissues were used. The release of soluble metal (Co and Cr from CoCr particles and Fe from 316L SS) was markedly reduced with time under physiological conditions. CoCr particles released far more Co than Cr. The biological responses to aged and freshly produced particles were tested using human monocytes because wear particles are usually associated with this type of cell in the periarticular tissues. Aged particles of both metals were markedly less toxic to monocytes than freshly produced particles. Aged particles also appeared to stimulate the release of more IL-6 and prostaglandin E(2) from monocytes. The results show that CoCr and 316L SS particles become less toxic but may induce more bone resorbing mediators as they age in vivo.
Publisher: Elsevier BV
Date: 08-2008
Publisher: Elsevier BV
Date: 09-1999
DOI: 10.1016/S8756-3282(99)00176-3
Abstract: Interleukin-1 (IL-1) has been shown to promote osteoclast (OC) differentiation, in addition to acting as a survival factor for mature osteoclasts. In this study, we investigate the expression of IL-1 during human osteoclast formation, taking advantage of a recently reported in vitro culture system that generates human OC from precursors in the peripheral blood mononuclear cell (PBMC) fraction, in the presence of murine stromal cells. This system enabled us to use species-specific probes and immunoassays to determine the respective cytokine contributions of the stromal cell and hemopoietic cell populations. Formation of functional osteoclasts occurred in cocultures of human PBMC and ST-2 cells for up to 21 days in the presence of 1alpha,25(OH)2-vitamin D3, dexamethasone, and recombinant human macrophage colony-stimulating factor (rhM-CSF). Total RNA was prepared at intervals during the cocultures and reverse transcriptase-polymerase chain reaction (RT-PCR) was performed using primers designed to lify specifically the mRNA species corresponding to the respective murine or human IL-1alpha and IL-1beta isoforms. Using human-specific primers, it was found that the hemopoietic cell component expressed both IL-1alpha and IL-1beta mRNA. Specific measurement of secreted human IL-1beta protein showed greatly augmented levels in coculture compared with hemopoietic cells grown in the absence of ST-2 cells, consistent with the known signaling from stromal cells to hemopoietic cells during osteoclastogenesis. Specific detection of mouse mRNA products showed that the ST-2 stromal cells in the coculture also expressed mRNA corresponding to IL-1alpha and IL-1beta. The expression of both mouse and human IL-1 mRNA was found to decline over the course of the coculture, although the level of IL-1alpha mRNA relative to IL-1beta mRNA remained constant, indicating that the two isoforms were coregulated in both cell populations under these conditions. Importantly, the hemopoietic cells were found to influence strongly the IL-1 mRNA levels in ST-2 cells, such that mouse IL-1alpha and IL-1beta mRNA levels were greatly enhanced in coculture, compared with ST-2 cells alone. Secreted mouse IL-1beta protein was upregulated in coculture in parallel with mRNA levels. However, the absolute levels of mouse IL-1beta achieved were more than 20-fold lower than the human IL-1beta levels. Prostaglandin estradiol (PGE2) levels were measured and found to be greatly increased in the coculture compared with ST-2 cells or hemopoietic cells alone, consistent with evidence that IL-1 action in osteoclastogenesis is mediated by PGE2. These results provide novel evidence that bidirectional signaling between stromal and hemopoietic cells may be important in the generation of human osteoclasts.
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: Elsevier BV
Date: 02-2004
DOI: 10.1016/S0142-9612(03)00556-8
Abstract: Aseptic bone loss adjacent to orthopedic joint implants is a common cause of joint implant failure in humans. This study investigates the expression of key regulators of osteoclast formation, receptor activator NFkappaB (RANK), Receptor activator of NFkappaB ligand (RANKL) and osteoprotegerin (OPG), in the peri-implant tissues of patients with osteolysis compared with levels in synovial tissues from osteoarthritic and healthy subjects. Immunohistochemical studies demonstrated that significantly higher levels of RANKL protein (p<0.05) were found in the peri-implant tissues of patients with implant failure than in similar tissues from osteoarthritic and healthy subjects. In contrast, OPG protein levels were similar in all tissues. RANKL, expressed as mRNA and protein, was predominantly associated with cells containing wear particles. Dual labeling studies showed that the cells expressing RANKL protein were macrophages. In situ hybridization studies confirmed that mRNA encoding for these proteins is also expressed by cells in the peri-implant tissues. In addition, RANK mRNA was expressed in cells that contained wear particles. These findings show that abnormally high levels of RANKL are expressed in peri-implant tissues of patients with prosthetic loosening and that these abnormal levels of RANKL may significantly contribute to aseptic implant loosening.
Publisher: Oxford University Press (OUP)
Date: 2003
DOI: 10.1093/RHEUMATOLOGY/KEG047
Abstract: To demonstrate the expression of osteoprotegerin (OPG) and receptor activator of nuclear factor kappaB ligand (RANKL) in synovial tissue from rheumatoid arthritis (RA) patients, establish the cell lineage expressing OPG and compare the expression of OPG in RA, spondyloarthropathies, osteoarthritis and normal synovial tissue. Synovial biopsy specimens were obtained at arthroscopy from 16 RA and 12 spondyloarthropathy patients with active synovitis of a knee joint, six RA patients with no evidence of active synovitis, 10 patients with osteoarthritis and 18 normal subjects. Immunohistological analysis was performed using monoclonal antibodies (mAb) to detect OPG and RANKL expression. In addition, dual immunohistochemical evaluation was performed with lineage-specific monoclonal antibodies (macrophages, fibroblasts and endothelial cells) and OPG to determine the cell lineages expressing OPG. The sections were evaluated by computer-assisted image analysis and semiquantitative analysis. Two patterns of OPG expression were seen, one exclusively in endothelial cells and one expressed predominantly in macrophages in the synovial lining layer. Both patterns of OPG staining could be blocked with excess recombinant OPG. Endothelial and synovial lining expression of OPG was seen in all synovial tissues except those from patients with active RA. In contrast, RANKL expression was seen predominantly in synovial tissue from patients with active disease, mainly in sublining regions, particularly within areas of lymphocyte infiltration. OPG expression on macrophage type synovial lining cells as well as endothelial cells is deficient in RA patients with active synovitis, in contrast to that seen in spondyloarthropathy patients with active synovitis. This deficiency in OPG expression in the inflamed joint of RA patients may be important in the development of radiologically defined joint erosions.
Publisher: Elsevier BV
Date: 05-2006
Publisher: Springer Science and Business Media LLC
Date: 21-11-2017
DOI: 10.1007/S00011-017-1116-5
Abstract: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that results in both local and systemic bone erosion, causing significant joint deformities and functional disability. The increased number of synovial fibroblasts, inflammatory cells and osteoclasts in RA is associated with reduced apoptosis in these cells. The ability to modulate the cell proliferation or death (particularly apoptosis) is recognised for its immense therapeutic potential. Identifying new therapeutics to assist in stimulating apoptosis within the synovial joints therefore may be beneficial in reducing inflammation and bone loss in RA patients. In this review, the roles of anti-apoptotic proteins that are upregulated in RA synovial joints will be discussed in relation to their actions on bone destruction and inflammation. Evidence recently published suggests that intracellular apoptotic inhibitory molecules can be targeted by current or new therapeutics to reduce joint damage in RA. However, the therapeutics that target these molecules are yet to reach clinical trial stages. Even so it is evident that understanding the upregulation of anti-apoptotic molecules in RA is required to improve treatments currently available for RA patients.
Publisher: Elsevier BV
Date: 09-2004
Publisher: Elsevier BV
Date: 12-2013
Publisher: Wiley
Date: 24-06-2008
DOI: 10.1002/ART.23818
Abstract: To demonstrate the effect of treatment with disease-modifying agents on the expression of osteoprotegerin (OPG) and RANKL in the synovial tissue from rheumatoid arthritis (RA) patients and to correlate these changes with radiologic damage measured on sequential radiographs of the hands and feet. Synovial biopsy specimens were obtained at arthroscopy from 25 patients with active RA (16 of whom had a disease duration <12 months) before and at 3-6-month intervals after starting treatment with a disease-modifying agent. Immunohistologic analysis was performed using monoclonal antibodies to detect OPG and RANKL expression, with staining quantitated using computer-assisted image analysis and semiquantitative analysis techniques. Serial radiographs of the hands and feet were analyzed independently by 2 radiologists and a rheumatologist using the van der Heide modification of the Sharp scoring method. Thirteen patients achieved a low disease state as defined by a disease activity score 20% after disease-modifying antirheumatic drug (DMARD) treatment. Successful DMARD treatment resulted in an increase in OPG expression and a decrease in RANKL expression at the synovial tissue level, which correlated with a reduction in erosion scores measured on annual radiographs of the hands and feet. Successful treatment-induced modulation of OPG and RANKL expression at the synovial tissue level, resulting in a reduction in the RANKL:OPG ratio, is likely to have a significant impact on osteoclast formation and joint damage in patients with active RA.
Start Date: 2009
End Date: 2012
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2006
End Date: 2008
Funder: National Health and Medical Research Council
View Funded Activity