Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 285, Issue 41, Pages 31325-31336Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.087122
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Funding
- National Science Council [NSC 97-2314-B-002-060-MY3, NSC98-3111-B-002-009, NSC 96-2320-B-004-MY2, NSC 97-2320-B-039-039-MY3, NSC 98-2815-C-039-082-B]
- National Science Council of Taiwan [TMS-094-2-B-023]
- National Health Research Institutes, Taiwan [NHRI-EX97-9712BC]
- Department of Health Executive Yuan, Taiwan [DOH97-TD-G-111-024]
- China Medical University [CMU96-220, CMU96-189, CMU97-277]
- M.D. Anderson Cancer Center
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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 alpha(v)beta(3) is critical for CYR61-mediated BMP-2 expression and osteoblastic differentiation. We also found that integrin-linked kinase, which is downstream of the alpha(v)beta(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-2mRNA and protein expression, resulting in enhanced cell proliferation and osteoblastic differentiation through activation of the alpha(v)beta(3) integrin/integrin-linked kinase/ERK signaling pathway.
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