CYR61 regulates BMP-2-dependent osteoblast differentiation through the {alpha}v{beta}3 integrin/integrin-linked kinase/ERK pathway.
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 α(v)β(3) is critical for CYR61-mediated BMP-2 expression and osteoblastic differentiation. We also found that integrin-linked kinase, which is downstream of the α(v)β(3) 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 α(v)β(3) integrin/integrin-linked kinase/ERK signaling pathway.
Su
Jen-Liang
JL
Graduate Institute of Cancer Biology, College of Medicine, and the eGraduate Institute of Basic Medical Science, China Medical University, Taichung 404,Taiwan.
Chiou
Jean
J
Tang
Chih-Hsin
CH
Zhao
Ming
M
Tsai
Chun-Hao
CH
Chen
Pai-Sheng
PS
Chang
Yi-Wen
YW
Chien
Ming-Hsien
MH
Peng
Chu-Ying
CY
Hsiao
Michael
M
Kuo
Ming-Liang
ML
Yen
Men-Luh
ML
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000096:biosynthesis*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D055515:Cysteine-Rich Protein 61 / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D000099200:Scaffold Protein ILK
D055396:Bone Morphogenetic Protein 2; D055515:Cysteine-Rich Protein 61; D048049:Extracellular Signal-Regulated MAP Kinases; D039302:Integrin alphaVbeta3; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK; C525719:Bmp2 protein, mouse; C491850:CCN1 protein, mouse