Search

Osteoarthritis (OA), the most common form of arthritis in the world, is characterized by articular cartilage breakdown in synovial joints. There is evidence of low-grade inflammatory responses in OA, but their contribution to OA pathogenesis is unclear. Studies have demonstrated that dysregulated complement activity is involved in OA pathogenesis. The complement component, C1q, is known to regulate inflammation via mechanisms involving apoptotic cell clearance and macrophage activation. Thus, we hypothesized that C1q is a key negative regulator of inflammatory mechanisms in OA. Using a combination of NanoString-based mRNA quantification and Luminex-based analyses for cytokine profiling, we found that differentiation of human monocyte-derived macrophages in C1q-depleted serum followed by stimulation with cartilage debris resulted in enhanced pro-inflammatory (e.g., IL1β) and reduced anti-inflammatory (e.g,. IL10) cytokine expression and secretion compared to cells grown in normal human serum. To definitively establish a regulatory role for C1q in OA, we used a well-established destabilization of the medial meniscus (DMM) model of knee OA in genetically-deficient mice. We found that knees of C1q-deficient mice subjected to DMM developed worse OA pathologies including exacerbated cartilage damage, osteophyte formation and synovitis relative to C1q-sufficient mice. Our data suggest that C1q deficiency exacerbates inflammation and cartilage damage through mechanisms involving dysregulated macrophage activation. Understanding the precise mechanisms underlying C1q-mediated regulation of inflammation may lead to the identification of novel targets for the treatment of inflammatory diseases including OA.