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| Title: | BMP-4 induction of arrest and differentiation of osteoblast-like cells via p21CIP1 and p27KIP1 regulation |
| Other Titles: | BMP-4 Induction of Arrest and Differentiation of Osteoblast-Like Cells via p21(CIP1) and p27(KIP1) Regulation |
| Authors: | Chang, SF;Chang, TK;Peng, HH;Yeh, YT;Lee, DY;Yeh, CR;Zhou, J;Cheng, CK;Chang, CA;Chiu, JJ |
| Contributors: | Division of Medical Engineering Research |
| 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. |
| Date: | 2009-11 |
| Relation: | Molecular Endocrinology. 2009 Nov;23(11):1827-1838. |
| Link to: | http://dx.doi.org/10.1210/me.2009-0143 |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:000271210800009 |
| Cited Times(Scopus): | http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=70350460804 |
| Appears in Collections: | [裘正健] 期刊論文
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| SCP70350460804.pdf | | 424Kb | Adobe PDF | 1009 | View/Open |
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