The Relationship Between CCN3 and Rheumatoid Arthritis and Its Potential Therapeutic Value

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation, progressive joint destruction, and bone damage. Despite advances in disease-modifying antirheumatic drugs (DMARDs), unmet clinical needs arising from incomplete efficacy and safety concerns continue to drive the search for innovative therapeutic targets. Cellular communication network factor 3 (CCN3), a matricellular CCN family protein, is low in normal synovium but elevated in RA synovium and circulation, where it correlates with disease activity, anti-cyclic citrullinated peptide (anti-CCP) antibody titers, and IL-6. CCN3-associated effects may involve inflammatory-cell recruitment, fibroblast-like synoviocyte (FLS) activation and senescence, extracellular matrix (ECM) remodeling, cartilage degeneration, and osteoclastogenesis. Mechanistically, CCN3 may interact with RA-relevant NF-κB, Wnt/β-catenin, BMP/Smad, PI3K/Akt/mTOR, IL-6/JAK/STAT, Notch, and MAPK signaling networks. This review comprehensively examines the expression patterns, functional mechanisms, signaling pathways, and ongoing debates concerning CCN3 in RA and further explores its promise as a therapeutic target in preclinical research.