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 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
heparan sulfate proteoglycans. In the present review, we discuss the roles of the
CCN family proteins in regulating resident cells of the bone microenvironment. In vertebrate development, the CCN family plays a critical role in osteo/chondrogenesis and vasculo/angiogenesis. 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. Due to the important roles of
CCN family proteins in skeletal development, abnormal expression of CCN
proteins is related to the
tumorigenesis of primary bone
tumors such as
osteosarcoma,
Ewing sarcoma, and
chondrosarcoma. Additionally, emerging studies have suggested that CCN
proteins may affect progression of secondary metastatic bone
tumors by moderating the bone microenvironment. CCN
proteins could therefore serve as potential therapeutic targets for
drug development against primary and metastatic bone
tumors.