{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CCN3 (also known as NOV) is a multifunctional matricellular protein that regulates diverse cellular processes in development, tissue homeostasis, and disease. CCN3 can modulate cell differentiation and lineage commitment via interactions with key signaling pathways; for example, its binding to Notch1 enhances Notch signaling and suppresses myogenesis in mesenchymal cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In endothelial cells, CCN3 directly promotes adhesion, chemotaxis, and survival by engaging several integrin receptors, thereby acting as a potent inducer of angiogenesis in vivo."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In neural and glial cell contexts, CCN3 is up‐regulated in response to connexin43 expression, where it physically associates with the C‐terminal domain of Cx43 and contributes to growth control, further supporting its role as a modulator of intercellular communication."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In cutaneous wound healing, CCN3 is highly expressed in granulation tissue and acts on skin fibroblasts to support adhesion and directed migration through integrin engagement, while also modulating gene expression in concert with TGF‑β1 signals."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In the musculoskeletal system, CCN3 expression correlates with tumor differentiation and a higher metastatic risk in Ewing’s sarcoma, and, in cartilage, its upregulation in the absence of CCN2 is associated with reduced proliferation and delayed terminal differentiation, suggesting that CCN3 may antagonize CCN2‐mediated chondrocyte maturation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Furthermore, CCN3 plays an essential role in the regulation of human hematopoietic stem and progenitor cells, as its deficiency impairs stem cell function while its forced expression enhances primitive cellular activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " In cancer, CCN3 secreted by prostate tumor cells can modulate the tumor microenvironment by recruiting macrophages and skewing them toward a proangiogenic M2 phenotype, thereby contributing to tumor invasion and neovascularization."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Moreover, genetic studies in mice reveal that loss or mutation of CCN3 results in multiple developmental defects – including skeletal malformations, cardiomyopathy, muscle atrophy, and lens degeneration – underscoring its critical role in organogenesis and tissue integrity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Finally, in vascular smooth muscle cells, CCN3 suppresses cell proliferation and migration, thereby limiting neointimal thickening following vascular injury and highlighting its importance in maintaining vascular homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kei Sakamoto, Shunji Yamaguchi, R Ando, et al. 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