BMP-4 induction of arrest and differentiation of osteoblast-like cells via p21CIP1 and p27KIP1 regulation

Shun Fu Chang, Ting Kuo Chang, Hsin Hsin Peng, Yi Ting Yeh, Ding Yu Lee, Chiuan Ren Yeh, Jing Zhou, Cheng Kung Cheng, Cheng Allen Chang, Jeng Jiann Chiu

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48 Citations (Scopus)

Abstract

Cell cycle regulation by differentiation signals is critical for eukaryote development. We investigated the roles of bone morphogenetic protein (BMP)-4, an important stimulator of osteoblast differentiation and bone formation, in regulating cell cycle distribution in four osteoblast-like celllines and mouse primary osteoblasts, and the underlying mechanisms. In all cells used, BMP-4 induced G0/G1 arrest. The molecular basis of the BMP-4 effect was analyzed, and the presentation on molecular mechanism is focused on human MG63 cells. BMP-4 induced p21CIP1 and p27KIP1 expressions and hence cell differentiation but had no effects on the expressions of cyclins A, B1, D1, and E, cyclin-dependent protein kinase-2, -4, and -6. Using specific small interfering RNA (siRNA), we found that BMP-4-induced G 0/G1 arrest, and p21CIP1 and p27KIP1 expressions were mediated by BMP receptor type IA (BMPRIA)-specific Sma- and Mad-related protein (Smad)1/5. BMP-4 induced transient phosphorylations of ERK; transfection of MG63 cells with ERK2, but not ERK1, -specific siRNA inhibited the BMP-4-induced responses in MG63 cells. Pretreatment of MG63 cells with Arg-Gly-Asp-Ser, which blocks the cell-extracellular matrix interaction, or transfection with β3 integrin-specific siRNA inhibited BMP-4-induced ERK and Smad1/5 phosphorylations. BMP-4 induced transient increases in associations of β3-integrin with focal adhesion kinase and Shc, the dominant-negative mutants of which inhibited BMP-4-induced ERK and Smad1/5 phosphorylations. Our results indicate that BMP-4 induces G 0/G1 arrest and hence differentiation in osteoblast-like cells through increased expressions of p21CIP1 and p27 KIP1, which are mediated by BMPRIA-specific Smad1/5. The extracellular matrix/β3 integrin/ focal adhesion kinase/Shc/ERK2 signaling pathway is involved in these BMP-4-induced responses in osteoblast-like cells.

Original languageEnglish
Pages (from-to)1827-1838
Number of pages12
JournalMolecular Endocrinology
Volume23
Issue number11
DOIs
Publication statusPublished - Nov 1 2009
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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    Chang, S. F., Chang, T. K., Peng, H. H., Yeh, Y. T., Lee, D. Y., Yeh, C. R., Zhou, J., Cheng, C. K., Chang, C. A., & Chiu, J. J. (2009). BMP-4 induction of arrest and differentiation of osteoblast-like cells via p21CIP1 and p27KIP1 regulation. Molecular Endocrinology, 23(11), 1827-1838. https://doi.org/10.1210/me.2009-0143