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CYR61 regulates BMP-2-dependent osteoblast differentiation through the {alpha}v{beta}3 integrin/integrin-linked kinase/ERK pathway.

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 ?(v)?(3) is critical for CYR61-mediated BMP-2 expression and osteoblastic differentiation. We also found that integrin-linked kinase, which is downstream of the ?(v)?(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 ?(v)?(3) integrin/integrin-linked kinase/ERK signaling pathway.

SUBMITTER: Su JL

PROVIDER: S-EPMC2951207 | biostudies-other | 2010 Oct

REPOSITORIES: biostudies-other

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CYR61 regulates BMP-2-dependent osteoblast differentiation through the {alpha}v{beta}3 integrin/integrin-linked kinase/ERK pathway.

Su Jen-Liang JL 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

The Journal of biological chemistry 20100730 41

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 ...[more]

PMID: 20675382

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Project description:Myocyte differentiation involves complex interactions between signal transduction pathways and transcription factors. The estrogen-related receptors (ERRs) regulate energy substrate uptake, mitochondrial respiration, and biogenesis and may target structural gene programs in striated muscle. However, ERRα's role in regulating myocyte differentiation is not known. ERRα and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) are coordinately upregulated with metabolic and skeletal muscle-specific genes early in myogenesis. We analyzed effects of ERRα overexpression and loss of function in myogenic models. In C2C12 myocytes ERRα overexpression accelerated differentiation, whereas XCT790 treatment delayed myogenesis and resulted in myotubes with fewer mitochondria and disorganized sarcomeres. ERRα-/- primary myocytes showed delayed myogenesis, resulting in structurally immature myotubes with reduced sarcomeric assembly and mitochondrial function. However, sarcomeric and metabolic gene expression was unaffected or upregulated in ERRα-/- cells. Instead, ERRα-/- myocytes exhibited aberrant ERK activation early in myogenesis, consistent with delayed myotube formation. XCT790 treatment also increased ERK phosphorylation in C2C12, whereas ERRα overexpression decreased early ERK activation, consistent with the opposing effects of these treatments on differentiation. The transient induction of MAP kinase phosphatase-1 (MKP-1), which mediates ERK dephosphorylation at the onset of myogenesis, was lost in ERRα-/- myocytes and in XCT790-treated C2C12. The ERRα-PGC-1α complex activates the Dusp1 gene, which encodes MKP-1, and ERRα occupies the proximal 5' regulatory region during early differentiation in C2C12 myocytes. Finally, treatment of ERRα-/- myocytes with MEK inhibitors rescued normal ERK signaling and myogenesis. Collectively, these data demonstrate that ERRα is required for normal skeletal myocyte differentiation via modulation of MAP kinase signaling.

Dataset Information

CYR61 regulates BMP-2-dependent osteoblast differentiation through the {alpha}v{beta}3 integrin/integrin-linked kinase/ERK pathway.

Publications

CYR61 regulates BMP-2-dependent osteoblast differentiation through the {alpha}v{beta}3 integrin/integrin-linked kinase/ERK pathway.

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