CHIP protects rheumatoid arthritis progression by targeting TRAF6 in arthritis animal models

Carboxyl terminus of HSC70-interacting protein (CHIP) serves as a quality control protein that involves in inflammation and immunity, bone remodeling and tumorigenesis. However, the role of CHIP in joint disease such as rheumatoid arthritis (RA) is less explored.

Wild-type and Chip knockdown mice were used to establish a collagen-induced arthritis (CIA) model to assess arthritis progression through clinical index and histopathological markers (synovial hyperplasia, inflammatory infiltration and cartilage damage). SiRNA and lentivirus were respectively used to knockdown and overexpress CHIP in CIA fibroblast-like synoviocytes (FLS), investigating its regulatory effect on proliferation, migration, invasion and inflammation. Western blotting and immunofluorescence analysis were performed to assess the effect of CHIP on Tumor necrosis factor receptor-associated factor 6 (TRAF6) and to elucidate the underlying mechanism. Adeno-associated virus (AAV) mediated delivery of Chip was used to evaluate its therapeutic effects in CIA mice.

CHIP significantly decreased in the synovium of CIA mice and RA patients compare to control. CHIP deficiency exacerbated synovial inflammation, cartilage degradation, and bone erosion in CIA, further underscoring its protective role in joint homeostasis. Moreover, knockdown of CHIP promoted the proliferation, migration and expression of inflammatory cytokines in CIA-FLS, while CHIP overexpression in CIA-FLS showed the opposite results. Mechanistically, CHIP interacted with TRAF6 and promoted the degradation of TRAF6. CHIP inhibited the migration and pro-inflammatory phenotypes of CIA-FLS via TRAF6/p65 pathway. Further, AAV mediated CHIP gene therapy by intra-articular administration effectively attenuated the progression of CIA by inhibiting the synovial inflammation and expression of TRAF6.

Collectively, these findings demonstrated the critical regulatory role of CHIP in RA. Therefore, exploiting the protective effects of CHIP may represent a potential therapeutic strategy for RA.

These findings not only advance our understanding of CHIP's regulatory role in RA but also highlight the value of genetic animal models in orthopaedic drug discovery.