Smads, p38 and ERK1/2 are involved in BMP9-induced osteogenic differentiation of C3H10T1/2 mesenchymal stem cells
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Although previous studies have demonstrated that BMP9 is highly capable of inducing osteogenic differentiation of mesenchymal stem cells, the molecular mechanism involved remains to be fully elucidated. In this study, we showed that BMP9 simultaneously promotes the activation of Smad1/5/8, p38 and ERK1/2 in C3H10T1/2cells. Knockdown of Smad4 with RNA interference reduced nuclear translocation of Smad1/5/8, and disrupted BMP9-induced osteogenic differentiation. BMP9-induced osteogenic differentiation was blocked by p38 inhibitor SB203580, whereas enhanced by ERK1/2 inhibitor PD98059. SB203580 decreased BMP9-activated Smads singling, and yet PD98059 stimulated Smads singling in C3H10T1/2 cells. The effects of inhibitor were reproduced with adenovirus expressing siRNA targeted p38 and ERK1/2, respectively. Taken together, our findings revealed that Smads, p38 and ERK1/2 are involved in BMP9-induced osteogenic differentiation. Also, it is noteworthy that p38 and ERK1/2 may play opposing regulatory roles in mediating BMP9-induced osteogenic differentiation of C3H10T1/2 cells. [BMB reports 2012; 45(4): 247-252]
Abstract
Although previous studies have demonstrated that BMP9 is highly capable of inducing osteogenic differentiation of mesenchymal stem cells, the molecular mechanism involved remains to be fully elucidated. In this study, we showed that BMP9 simultaneously promotes the activation of Smad1/5/8, p38 and ERK1/2 in C3H10T1/2cells. Knockdown of Smad4 with RNA interference reduced nuclear translocation of Smad1/5/8, and disrupted BMP9-induced osteogenic differentiation. BMP9-induced osteogenic differentiation was blocked by p38 inhibitor SB203580, whereas enhanced by ERK1/2 inhibitor PD98059. SB203580 decreased BMP9-activated Smads singling, and yet PD98059 stimulated Smads singling in C3H10T1/2 cells. The effects of inhibitor were reproduced with adenovirus expressing siRNA targeted p38 and ERK1/2, respectively. Taken together, our findings revealed that Smads, p38 and ERK1/2 are involved in BMP9-induced osteogenic differentiation. Also, it is noteworthy that p38 and ERK1/2 may play opposing regulatory roles in mediating BMP9-induced osteogenic differentiation of C3H10T1/2 cells. [BMB reports 2012; 45(4): 247-252]
참고문헌 (25)
- Deng, Z. L., "Regulation of osteogenic differentiation during skeletal development", Frontiers Biosci., 13, pp.2001~2021 (2008)
- Hogan, B. L., "Bone morphogenetic proteins: multifunctional regulators of vertebrate development", Genes Dev., 10, pp.1580~1594 (1996)
- Chen, D., "Bone morphogenetic proteins", Growth Factors, 22, pp.233~241 (2004)
- Boraiah, S., "Complications of recombinant human BMP-2 for treating complex tibial plateau fractures: a preliminary report", Clin. Orthop. Relat. Res., 467, pp.3257~3262 (2009)
- Rutherford, R. B., "Bone morphogenetic protein 7 ex vivo gene therapy", Drug News Perspect, 16, pp.5~10 (2003)
- Kang, Q., "Characterization of the distinct orthotopic boneforming activity of 14 BMPs using recombinant adenovirusmediated gene delivery", Gene Ther., 11, pp.1312~1320 (2004)
- Luu, H. H., "Distinct roles of bone morphogenetic proteins in osteogenic differentiation of mesenchymal stem cells", J. Orthop. Res., 25, pp.665~677 (2007)
- Luo, J., "TGFbeta", BMP type I receptors ALK1 and ALK2 are essential for BMP9-induced osteogenic signaling in mesenchymal stem cells, 2010, pp.285, 29588~29598
- Wu, N., "Identification and analysis of type II TGF-{beta} receptors in BMP-9- induced osteogenic differentiation of C3H10T1", 2 mesenchymal stem cells, 2010, pp.42, 699~708
- Heldin, C. H., "TGF-beta signaling from cell membrane to nucleus through SMAD proteins", Nature, 390, pp.465~471 (1997)
- Chang, S. F., "BMP-4 induction of arrest and differentiation of osteoblast- like cells via p21 CIP1 and p27 KIP1 regulation", Mol. Endocrinol., 23, pp.1827~1838 (2009)
- Gallea, S., "Activation of mitogen-activated protein kinase cascades is involved in regulation of bone morphogenetic protein-2-induced osteoblast differentiation in pluripotent C2C12 cells", Bone, 28, pp.491~498 (2001)
- Nöth, U., "Activation of p38 and Smads mediates BMP-2 effects on human trabecular bone-derived osteoblasts", Exp. Cell Res., 291, pp.201~211 (2003)
- Celil, A. B., "BMP-2 and insulin-like growth factor-I mediate Osterix (Osx) expression in human mesenchymal stem cells via the MAPK and protein kinase D signaling pathways", J. Biol. Chem., 280, pp.31353~31359 (2005)
- Cargnello, M., "Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases", Microbiol. Mol. Biol. Rev., 75, pp.50~83 (2011)
- Verheyen, E. M., "Opposing Effects of Wnt and MAPK on BMP", Smad Signal Duration, 2007, pp.13, 755~756
- Miyazono, K., "Bone morphogenetic protein receptors and signal transduction", J. Biochem., 147, pp.35~51 (2010)
- Song, J. J., "Bone morphogeneticprotein-9 binds to liver cells and stimulates proliferation", Endocrinology, 136, pp.4293~4297 (1995)
- López-Coviella, I., "Induction and maintenance of the neuronal cholinergic phenotype in the central nervous system by BMP9", Science, 289, pp.313~316 (2000)
- Chen, C., "An integrated functional genomics screening program reveals a role for BMP-9 in glucose homeostasis", Nat. Biotechnol., 21, pp.294~301 (2003)
- Truksa, J., "Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferring receptor 2 (Tfr2), and IL-6", Proc. Natl. Acad. Sci. U.S.A., 103, pp.10289~10291 (2006)
- Cao, X., "The BMP signaling and in vivo bone formation", Gene, 357, pp.1~8 (2005)
- Heffron, D. S., "Opposing roles of ERK and p38 MAP kinases in FGF2-induced astroglial process extension", Mol. Cell Neurosci., 28, pp.779~790 (2005)
- Shields, J. M., "Opposing roles of the extracellular signal-regulated kinase and p38 mitogen-activated protein kinase cascades in Ras-mediated downregulation of tropomyosin", Mol. Cell Biol., 22, pp.2304~2317 (2002)
- Payne, K. A., "Effect of phosphatidyl inositol 3-kinase, extracellularsignal-regulated kinases 1", 2, and p38 mitogen-activated proteinkinase inhibition on osteogenic differentiation of muscle-derived stem cells, 2010, pp.16, 3647~3655