CYR61 Regulates BMP-2-dependent Osteoblast Differentiation through the avb3 Integrin/Integrin-linked Kinase/ERK Pathway

• Published in: The Journal of biological chemistry 2010-10, Vol.285 (41), p.31325-31336
• Main Authors: Su, Jen-Liang, Chiou, Jean, Tang, Chih-Hsin, Zhao, Ming, Tsai, Chun-Hao, Chen, Pai-Sheng, Chang, Yi-Wen, Chien, Ming-Hsien, Peng, Chu-Ying, Hsiao, Michael, Kuo, Ming-Liang, Yen, Men-Luh
• Format: Article
• Language: English
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M109.087122

Osteoporosis is one of the most common bone pathologies. A number of novel molecules have been reported to increase bone formation including cysteine-rich protein 61 (CYR61), a ligand of integrin receptor, but mechanisms remain unclear. It is known that bone morphogenetic proteins (BMPs), especially BMP-2, are crucial regulators of osteogenesis. However, the interaction between CYR61 and BMP-2 is unclear. We found that CYR61 significantly increases proliferation and osteoblastic differentiation in MC3T3-E1 osteoblasts and primary cultured osteoblasts. CYR61 enhances mRNA and protein expression of BMP-2 in a time- and dose-dependent manner. Moreover, CYR61-mediated proliferation and osteoblastic differentiation are significantly decreased by knockdown of BMP-2 expression or inhibition of BMP-2 activity. In this study we found integrin avb3 is critical for CYR61-mediated BMP-2 expression and osteoblastic differentiation. We also found that integrin-linked kinase, which is downstream of the avb3 receptor, is involved in CYR61-induced BMP-2 expression and subsequent osteoblastic differentiation through an ERK-dependent pathway. Taken together, our results show that CYR61 up-regulates BMP-2 mRNA and protein expression, resulting in enhanced cell proliferation and osteoblastic differentiation through activation of the avb3 integrin/integrin-linked kinase/ERK signaling pathway.