Abstract
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.
Highlights
Bone is a mineralized tissue that underlies multiple mechanical and metabolic functions of the skeleton [1]
Recombinant cysteine-rich protein 61 (CYR61) Protein Induced Differentiation in MC3T3E1 Cells—In this study we investigated the role of CYR61 in osteoblast proliferation and differentiation
We found that treatment with recombinant CYR61 (rCYR61) protein significantly increased proliferation of mouse osteoblast MC3T3-E1 cells in a dose-dependent manner to ϳ200 ng/ml (Fig. 1A), after which
Summary
Bone is a mineralized tissue that underlies multiple mechanical and metabolic functions of the skeleton [1]. ␣v3 integrin/integrin-linked kinase (ILK)/extracellular signal-regulated kinase (ERK) signaling pathways are involved in CYR61-mediated induction of BMP-2 expression and subsequent cell proliferation and osteoblastic differentiation. Our data showed that rCYR61-induced osteoblast proliferation and migration activity were significantly decreased after treatment with neutralizing BMP-2 antibodies for indicated times and dosages (Fig. 3A).
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