The CCN family of proteins is composed of six extracellular matrix-associated proteins that play crucial roles in skeletal development, wound healing, fibrosis and cancer. Members of the CCN family proteins share four conserved cysteine-rich modular domains that trigger signal transduction in cell adhesion, migration, proliferation, differentiation, and survival through direct binding to specific integrin receptors and heparin sulfate proteoglycans. These effects are regulated through signaling via integrins, bone morphogenetic protein, vascular endothelial growth factor, Wnt and Notch via direct binding to CCN family proteins. Additionally, emerging studies have suggested that CCN proteins may affect progression of secondary metastatic bone tumours by moderating the bone microenvironment.
The CCN proteins are key signalling and regulatory molecules involved in many vital biological functions, including cell proliferation, angiogenesis, tumourigenesis and wound healing. How these proteins influence such a range of functions remains incompletely understood but is probably related to their discrete modular nature and a complex array of intra- and inter-molecular interactions with a variety of regulatory proteins and ligands. Although certain aspects of their biology can be attributed to the four individual modules that constitute the CCN proteins, recent results suggest that some of their biological functions require cooperation between modules. Indeed, the modular structure of CCN proteins provides important insight into their structure–function relationships.
The CCN proteins regulate cell adhesion, migration, proliferation, and differentiation to modulate variant biological functions including tumorigenesis, chondrogenesis, osteogenesis, angiogenesis, apoptosis, and hematopoiesis. As expected from matricellular proteins modulating ECM signaling, the most familiar functions of CCN family proteins are their roles in cell adhesion and migration. The mechanism of CCN proteins regulating cell fates varies in different cell types. CCN proteins inhibit cell proliferation and increase apoptosis and its abnormal expression is associated with cancer progression. Bone is a complex tissue composed of two major cell types, bone resorption osteoclasts and bone formation osteoblasts, responsible for bone remodeling. Evidence suggests that CCN proteins regulate the differentiation of these cells (osteoblasts and osteoclast). CCN proteins are tightly regulated in osteogenic cell lineages and are involved in skeletogenesis. Abnormal levels or altered forms of CCN proteins are associated with tumor progression
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