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PMID:20675382

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Citation

Su, JL, Chiou, J, Tang, CH, Zhao, M, Tsai, CH, Chen, PS, Chang, YW, Chien, MH, Peng, CY, Hsiao, M, Kuo, ML and Yen, ML (2010) CYR61 regulates BMP-2-dependent osteoblast differentiation through the {alpha}v{beta}3 integrin/integrin-linked kinase/ERK pathway. J. Biol. Chem. 285:31325-36

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.

Links

PubMed PMC2951207 Online version:10.1074/jbc.M109.087122

Keywords

Animals; Bone Morphogenetic Protein 2/biosynthesis; Cell Differentiation/drug effects; Cell Differentiation/physiology; Cell Line; Cell Proliferation/drug effects; Cysteine-Rich Protein 61/metabolism; Cysteine-Rich Protein 61/pharmacology; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases/metabolism; Gene Expression Regulation, Enzymologic/drug effects; Gene Expression Regulation, Enzymologic/physiology; Integrin alphaVbeta3/metabolism; MAP Kinase Signaling System/drug effects; MAP Kinase Signaling System/physiology; Mice; Osteoblasts/cytology; Osteoblasts/metabolism; Protein-Serine-Threonine Kinases/metabolism; Time Factors

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:CCN1

involved_in

GO:0033690: positive regulation of osteoblast proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCN1

involved_in

GO:0030513: positive regulation of BMP signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P21274

P

Seeded From UniProt

complete

HUMAN:CCN1

involved_in

GO:0030501: positive regulation of bone mineralization

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCN1

involved_in

GO:0030335: positive regulation of cell migration

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCN1

involved_in

GO:0001934: positive regulation of protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCN1

involved_in

GO:0070372: regulation of ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCN1

involved_in

GO:0044319: wound healing, spreading of cells

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCN1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCN1

involved_in

GO:0045860: positive regulation of protein kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCN1

involved_in

GO:0045669: positive regulation of osteoblast differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ITB3

involved_in

GO:0033690: positive regulation of osteoblast proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ITB3

involved_in

GO:0030335: positive regulation of cell migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ITAV

involved_in

GO:0033690: positive regulation of osteoblast proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ITAV

involved_in

GO:0030335: positive regulation of cell migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NOGG

involved_in

GO:0030336: negative regulation of cell migration

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NOGG

involved_in

GO:0045668: negative regulation of osteoblast differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:BMP2

involved_in

GO:0045669: positive regulation of osteoblast differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:BMP2

involved_in

GO:0030501: positive regulation of bone mineralization

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:BMP2

involved_in

GO:0030335: positive regulation of cell migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:BMP2

involved_in

GO:0033690: positive regulation of osteoblast proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CYR61

involved_in

GO:0001934: positive regulation of protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CYR61

involved_in

GO:0030335: positive regulation of cell migration

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CYR61

involved_in

GO:0030513: positive regulation of BMP signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P21274

P

Seeded From UniProt

complete

HUMAN:CYR61

involved_in

GO:0033690: positive regulation of osteoblast proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CYR61

involved_in

GO:0044319: wound healing, spreading of cells

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CYR61

involved_in

GO:0045669: positive regulation of osteoblast differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CYR61

involved_in

GO:0045860: positive regulation of protein kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CYR61

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CYR61

involved_in

GO:0070372: regulation of ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CYR61

involved_in

GO:0030501: positive regulation of bone mineralization

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ILK

involved_in

GO:0030513: positive regulation of BMP signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ILK

involved_in

GO:0045669: positive regulation of osteoblast differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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