UCLA

Members of the C(Cyr61) C(CTGF) N(Nov) family of matricellular proteins are involved in multiple aspects of embryonic and postnatal development and disease pathologies. CCN2, or connective tissue growth factor, is the second member of the family and has gained importance due to its prominent role in fibrotic disease. CCN2 has been extensively studied both in vitro and in vivo, but its specific roles remain unclear due to discrepancies in cell specific signaling mechanisms and experimental design. The current use of CCN2 blocking antibodies in clinical trials to treat symptoms associated with fibrosis and kidney function during diabetes warrants a clearer understanding of the function of CCN2 during normal physiology in order anticipate side effects. In order to investigate the functions of CCN2 during development, we have further analyzed the Ccn2 global knockout mouse and found that CCN2 plays essential roles in angiogenesis during vascular remodeling and cellular stress during endochondral ossification. CCN2 plays a dual role in vascular remodeling, first through mediating platelet derived growth factor (PDGF) signaling between endothelial cells and pericytes, and second through inducing the secretion of provisional and permanent vascular basement membrane components. Further analysis of the ECM defect observed in the growth plates of Ccn2 mutant mice revealed that the loss of CCN2 results in increased endoplasmic reticulum (ER) stress. Ccn2 mutants also exhibited decreased Nuclear Factor κB (NFκB) and autophagy-mediated cellular survival. Conversely, the overexpression of CCN2 results in attenuated ER stress and increased cellular survival during chemically induced ER stress. These results highlight a novel protective role for CCN2 during chondrocyte differentiation. Taken together, these results demonstrate that CCN2 plays important physiological roles in vivo and these roles should be considered during therapeutic interventions.