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Despite advances in disease\u2010modifying 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\u20093 (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\u2010cyclic citrullinated peptide (anti\u2010CCP) antibody titers, and IL\u20106. CCN3\u2010associated effects may involve inflammatory\u2010cell recruitment, fibroblast\u2010like synoviocyte (FLS) activation and senescence, extracellular matrix (ECM) remodeling, cartilage degeneration, and osteoclastogenesis. Mechanistically, CCN3 may interact with RA\u2010relevant NF\u2010\u03baB, Wnt\/\u03b2\u2010catenin, BMP\/Smad, PI3K\/Akt\/mTOR, IL\u20106\/JAK\/STAT, Notch, and MAPK signaling networks. 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