Mechanical Load-Induced Articular Collagen Remodeling as a Potential Therapeutic Target for Rheumatoid Arthritis
Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease affecting joints. Women are twice as likely to develop RA, and increasing age is another risk factor1. RA has a multifactorial etiology but is characterized by autoantibodies that target citrullinated proteins, leading to inflammatory cells infiltrating and secreting cytokines in the synovium2,3,4. Clinical manifestations of RA include joint arthralgia and swelling, potentially leading to gross joint deformity and extraarticular symptoms5,6. Normal mechanical stress to joints results in collagen remodeling and local inflammation, however, accelerated collagen remodeling is associated with RA disease progression7,8,9. Understanding the mechanism of joint damage in RA is clinically significant to determining treatment, including developing therapeutics that target the relevant steps in this process. It has been suggested that the mechanism of tocilizumab, an existing and effective treatment for RA, involves a dose-dependent reduction in collagen turnover to prevent joint damage9. Methods: In a study of mice with mutated Col11a1, which codes for type IX collagen in articular cartilage. This mutation induced joint morphology that mimicked joints in RA and osteoarthritis (OA), characterized by thinner and less dense cortical bone and thicker articular cartilage due to proteoglycan loss. Tibias were isolated from mutated and wild-type mice and cyclically compressed for 1, 2, and 6 weeks at 4.5 N (low) and 9 N (high) loads. The tibias were then analyzed using histology, microcomputed tomography, and immunohistochemistry9. In a similar study, patellas were isolated from mice (n=48) and exposed to axial (200 N) and axial with shear (500 N normal and induced shear) forces, cultured for 0, 3, 7, or 14 days, and analyzed using quantitative PCR10. Results: The study of Col11a1 mutated mice, after cyclical loading, showed that the Col11a1 mutation resulted in less cartilage damage, demonstrated by increased cartilage thickness. The Col11a1 mutated mice also showed decreased MMP (matrix metalloprotease) levels, which degrade collagen9. In the sheared patellas study, there was significantly reduced type II collagen expression in sheared patellas (0.4 and 0.19 fold change at days 0 and 7, respectively). The sheared patellas also showed elevated apoptotic gene Fas expression and chondrocyte-derived degradative enzymes10. Conclusions: Reduced type IX collagen expression could be protective by resulting in cartilage swelling secondary to water influx. However, overall degradation of the collagen microstructure may encourage inflammatory cell infiltration, perpetuating the joint damage seen in RA. Therefore, collagen remodeling may be an effective target for RA therapy.
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