Pathogenesis Of Bone Erosions Research Articles

Association between RANK, RANKL and OPG polymorphisms with ACPA and erosions in rheumatoid arthritis: results from a meta-analysis involving three French cohorts.

ObjectivesThe RANK/RANKL/osteoprotegerin (OPG) system plays a central role in the pathogenesis of bone erosions in rheumatoid arthritis (RA). The aim of this study was to test the association between 11 single-nucleotide polymorphisms (SNPs) located on RANK, RANKL and OPG genes and anticitrullinated peptide antibody (ACPA) presence or erosions in RA.MethodsPatients: This work was performed on three independent samples of French patients with RA: the Etude de Suivi des PolyArthrites Indifférenciées Récentes (ESPOIR) (n=632), Rangueil Midi-Pyrénées (RMP) (n=249) and French Rheumatoid Arthritis Genetic Consortium (FRAGC) (n=590) cohorts. Genotyping: the genotyping of 11 SNPs located on RANK, RANKL and OPG were performed by PCR. Statistical analyses: The association between the genotypes with ACPA or erosions was first tested in the ESPOIR cohort using a χ2 test and, in the case of significant association, replicated in the RMP and FRACG cohorts. A meta-analysis on the three cohorts was performed using the Mantel-Haenszel method.ResultsOne SNP on RANK (rs8086340) and three SNPs on RANKL (rs7984870, rs7325635, rs1054016) were significantly associated with ACPA presence, while one SNP on OPG (rs2073618) and one SNP on RANKL (rs7325635) were significantly associated with erosions in the ESPOIR cohort. Following meta-analysis performed on the three samples, the SNP on RANK and the GGG haplotype of the three SNPs located on RANKL were both significantly associated with ACPA presence, while only the SNP on OPG remained significantly associated with erosions.ConclusionsThis study identified one SNP located on RANK, one haplotype on RANKL associated with ACPA presence, and one SNP located on OPG associated with erosions in three different samples of French patients with RA.

Pathogenesis of Bone Erosions in Rheumatoid Arthritis: Not Only Inflammation

It is a matter of fact that the inflammatory pathogenesis does not explain all the skeletal manifestations of Rheumatoid Arthritis (RA), and the development of bone involvement is sometimes unconnected from the clinical scores of inflammation. On the basis of recent studies, we would like to make a point of the new available evidence about the metabolic pathogenic component of bone erosions. We assume that in this process an additional role could be played by metabolic factors, such as the parathyroid hormone (PTH), DKK1 (the inhibitor of the Wnt/β catenin pathway) and cortical bone mineral density. The result is a new pathogenic hypothesis for bone erosion in RA, which supplements the inflammatory one: the reduction of osteoblasts activity and the increase of the osteoclasts one, involved in the pathogenesis of bone erosions and osteoporosis, are not only the consequence of the action of inflammatory cytokines, but also of increased levels of DKK1 and PTH. On the other hand, osteoporosis, in particular at the cortical sites, facilitates the appearance of erosions.

Epigenetics in Rheumatoid Arthritis: A Primer for Rheumatologists

Epigenetic anomalies are emerging as key pathogenic features of rheumatoid arthritis (RA). The effect of epigenetics in RA ranges from contributing to complex disease mechanisms to identifying biomarkers for early diagnosis and response to therapy. This review focuses on three key epigenetic areas in RA, namely DNA methylation, histone modification, and expression and/or function of microRNAs. Epigenomics studies of DNA methylation have identified alterations of genome-wide DNA methylation in cells from patients with rheumatoid arthritis. Histone modification studies have focused on histone acetylation, which tends to be increased in RA. Preclinical studies show that inhibitors of histone deacetylases are effective in cellular and animal models of RA. Genome-wide and candidate microRNA surveys identified increased or reduced expression of selected microRNAs in rheumatoid arthritis. These microRNA are either pro or anti-inflammatory in multiple cell types or affect osteoclast physiology and the pathogenesis of bone erosion. Defining epigenetic contributions to the pathogenesis of RA, especially in combination with understanding genetic associations, could lead to novel therapy and a clearer understanding of disease risk.

Nutritional Antioxidants and Lipid Profile in Newly Diagnosed Rheumatoid Arthritis Patients

Introduction: Rheumatoid arthritis (RA) is a chronic progressive autoimmune disorder characterized by symmetric erosive synovitis. The pathogenesis of bone erosion and joint deformities are not fully understood. The aim of this study was to find out vitamin C and E levels along with the lipid profile in newly diagnosed cases of RA. Materials and Methods: The patients for the study were selected from individuals attending the routine checkup in an Outpatient Department. Based on the criteria led by the American Rheumatism Association (ARA), the newly diagnosed patients were taken as cases and other normal individuals were taken as control group in the study. A total of 50 subjects were included in the study with the age group of 48 ± six years for both genders. Serum Vitamin-E was determined by the colorimetric method and serum Vitamin-C was estimated by the dinitro phenyl hydrazine method. Serum total cholesterol, HDL-cholesterol, triglycerides, and VLDL levels were estimated by the enzymatic method. LDL- cholesterol was calculated by the Friedewald's formula. Results: The levels of nutritional antioxidants vitamin E and C were different significantly in RA patients compared to control group. The lipid profile parameters were also different significantly in RA patients compared to the controls. Conclusion: Patients with RA presented with an imbalance in the oxidant-antioxidant system that markedly increased lipid peroxidation products and significantly decreased lipid soluble antioxidant vitamin E. These changes might play a role in the tissue damage and inflammation process in this disease.

Clinical images: Divergent patterns of joint remodeling following effective urate‐lowering therapy in tophaceous gout

The patient, a 35-year-old man, presented with severe tophaceous gout and hyperuricemia (10.2 mg/dl), despite receiving combination treatment with allopurinol (300 mg daily) and benzbromarone (100 mg daily). He had a history of renal transplantation and was treated with cyclosporine; his serum creatinine level was 2.07 mg/dl. During a prolonged hospital admission in 2007 for treatment of an infected tophus affecting the calf, monthly administration of rasburicase (1) was initiated, leading to normalization of the serum urate levels (3.8–6.0 mg/dl) and a gradual reduction in tophus size. Baseline radiography showed large gouty erosions, particularly affecting the left middle finger proximal interphalangeal (PIP) joint and the right first metatarsophalangeal (MTP) joint (arrows in left panels of A and B). After 2 years of treatment with rasburicase, repeat radiography in 2009 showed some regression in the soft tissue masses and divergent patterns of joint remodeling at different sites, with collapse and telescoping of the left middle finger PIP joint, and new bone formation with ankylosis at the right first MTP joint (arrows in right panels of A and B). Osteoblast-mediated bone resorption and enhanced osteoclastogenesis have previously been implicated in the pathogenesis of bone erosion in chronic tophaceous gout (2,3). These images suggest that resorption of tophi may alter these cellular processes in contrasting ways, leading to different patterns of bone remodeling.

A combination of methotrexate and zoledronic acid prevents bone erosions and systemic bone mass loss in collagen induced arthritis

IntroductionOsteoclasts play a key role in the pathogenesis of bone erosion and systemic bone mass loss during rheumatoid arthritis (RA). In this study, we aimed to determine the effect of methotrexate (MTX) and zoledronic acid (ZA), used alone or in combination, on osteoclast-mediated bone erosions and systemic bone mass loss in a rat model of collagen induced arthritis (CIA). We hypothesized that MTX and ZA could have an additive effect to prevent both bone erosion and systemic bone loss.MethodsArthritis was induced in 64 female Sprague-Dawley rats. After the clinical onset of CIA, rats were assigned to treatment with MTX (1 mg/kg/week), ZA (100 μg/kg twice weekly), both treatments at the same regimens, or vehicle. Arthritis score and paw thickness were recorded twice weekly. The rats were sacrificed on D28 and hind paws were removed for radiographic, histological and immunohistochemical analysis. The effects of treatments on osteoclastogenesis were determined by Tartrate resistant acid phosphatase (TRAP) staining. Micro-CT of the tibia was carried out for histomorphometric analysis. Bone mass density was evaluated by densitometry.ResultsMTX significantly decreased the severity of CIA, whereas ZA slightly exacerbated it. When these two drugs were used in combination, MTX prevented the pro-inflammatory effect of ZA. The combination of ZA with MTX was more effective than MTX alone for reducing structural joint damage with a dramatic decrease of osteoclasts' number in the eroded joints. However, MTX alone also significantly reduced the number of osteoclasts and the number of CD68+ mononuclear cells. ZA alone, or ZA with MTX, significantly increased the systemic bone mass density measured by densitometry and bone volume on histomorphometric analysis.ConclusionsA combination of MTX and ZA prevented both bone erosion and systemic bone loss in a rat model of arthritis. Both treatments independently decreased the number of osteoclasts in the eroded joint. However, while MTX probably acts mainly through a decrease of inflammation, ZA has a direct effect on osteoclasts, allowing a dramatic down-regulation of these cells in inflamed joints. These two different mechanisms of action provide support for the use of a combination of these two drugs to improve the prevention of structural joint damage in RA.

Bone destruction in arthritis

Rheumatoid arthritis (RA) is characterised by the presence of an inflammatory synovitis accompanied by destruction of joint cartilage and bone. Destruction of cartilage matrix results predominantly from the action of...

TRANCE/RANKL Knockout Mice Are Protected from Bone Erosion in a Serum Transfer Model of Arthritis

There is considerable evidence that osteoclasts are involved in the pathogenesis of focal bone erosion in rheumatoid arthritis. Tumor necrosis factor-related activation-induced cytokine, also known as receptor activator of nuclear factor-kappaB ligand (TRANCE/RANKL) is an essential factor for osteoclast differentiation. In addition to its role in osteoclast differentiation and activation, TRANCE/RANKL also functions to augment T-cell dendritic cell cooperative interactions. To further evaluate the role of osteoclasts in focal bone erosion in arthritis, we generated inflammatory arthritis in the TRANCE/RANKL knockout mouse using a serum transfer model that bypasses the requirement for T-cell activation. These animals exhibit an osteopetrotic phenotype characterized by the absence of osteoclasts. Inflammation, measured by clinical signs of arthritis and histopathological scoring, was comparable in wild-type and TRANCE/RANKL knockout mice. Microcomputed tomography and histopathological analysis demonstrated that the degree of bone erosion in TRANCE/RANKL knockout mice was dramatically reduced compared to that seen in control littermate mice. In contrast, cartilage erosion was present in both control littermate and TRANCE/RANKL knockout mice. These results confirm the central role of osteoclasts in the pathogenesis of bone erosion in arthritis and demonstrate distinct mechanisms of cartilage destruction and bone erosion in this animal model of arthritis.