Inhibition of Cathepsin C attenuates osteoarthritis by modulating macrophage activated status and reducing tissue inflammatory responses.

Aims: Osteoarthritis (OA) is a common degenerative joint disease, with growing evidence suggesting that chronic inflammation plays a critical role in its progression. Targeting chronic inflammation could potentially slow OA development. While Cathepsin C (CatC) has been widely studied in the context of inflammatory diseases, its specific role in OA remains underexplored. Methods: To address this question, we used clinical samples of OA patients and a murine OA model to clarify the expression of CatC and its role in OA. By further isolating and culturing OA-related primary cells, we aimed to identify the source of CatC and determine its impact on various cell types. In addition, we used CatC knockdown mice and specific CatC inhibitors AZD7986 to verify the impact of CatC inhibition on OA progress. Results: Our results demonstrated that CatC expression was significantly upregulated in OA synovium, with infiltrated macrophages playing a crucial role in this upregulation. Furthermore, CatC was identified as a key factor in promoting the release of inflammatory mediators by facilitating the polarization of macrophages towards pro-inflammatory activation state. In turn, macrophage-derived CatC exacerbated inflammation and cartilage degradation through paracrine effects on synovial fibroblasts and chondrocytes. Knockdown of CatC or administration of the specific CatC inhibitor AZD7986 mitigates cartilage damage and synovial inflammation by reducing the expression of inflammatory factors and matrix-degrading enzymes. Conclusion: This study demonstrates that macrophage-derived CatC contributes to OA progression through upregulation of inflammatory mediators and MMP13. These findings suggest that CatC may represent a potential therapeutic target warranting further investigation.