CCN2 (cellular communication network factor 2) is a secreted matricellular protein that functions as a critical hub in connective tissue development and pathological remodeling. Physiologically, CCN2 promotes osteoblast differentiation and osteogenesis through TGFBR/SMAD signaling 1, while also mediating cell adhesion and proliferation in fibroblasts, endothelial cells, and chondrocytes 2. The protein operates through multiple signaling cascades including ERK1/2, JNK, and integrin-dependent pathways 2. Pathologically, CCN2 drives fibrotic disease progression across multiple tissues. In knee arthrofibrosis, CCN2 expression is induced by TGF-β signaling in fibroblasts activated through macrophage interaction, promoting fibroblast pro-fibrotic functions and correlating with collagen deposition 3. In osteoarthritis, CCN2 facilitates IL-17 production and osteoclastogenesis via miR-655 inhibition 4. CCN2 also contributes to breast cancer osteolytic bone metastasis 5, APS vasculopathy through YAP1-mediated vascular smooth muscle cell proliferation 6, and atherosclerotic plaque vulnerability via endothelial-to-mesenchymal transition 7. Germline CCN2 variants cause spondyloepimetaphyseal dysplasia with low bone mass through impaired protein secretion and reduced osteogenic stimulation 1. CCN2 inhibition shows therapeutic potential in pulmonary fibrosis 8, making it a promising biomarker and therapeutic target across fibrotic and inflammatory diseases.