Fibroblast growth factor 2 induction of the osteocalcin gene requires MAPK activity and phosphorylation of the osteoblast transcription factor, Cbfa1/Runx2
Fibroblast growth factor 2 induction of the osteocalcin gene requires MAPK activity and phosphorylation of the osteoblast transcription factor, Cbfa1/Runx2
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DOI：
10.1074/jbc.m206057200
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发表时间：
2002-09-27
影响因子：
4.8
通讯作者：
Franceschi, RT
中科院分区：
文献类型：
--
作者：
Xiao, GZ;Jiang, D;Franceschi, RT
成纤维细胞生长因子2是骨形成和成骨细胞活性的重要调节因子。然而，它对骨细胞的作用机制在很大程度上是未知的。成纤维细胞生长因子信号转导的一个主要途径是通过丝裂原活化蛋白激酶(MAPK)途径。我们最近发现，这个途径对于成骨细胞相关转录因子Cbfa1/Runx2的激活和磷酸化是重要的(肖，G.，酱，D.，Thomas，P.，Benson，M.D.，Guan，K.，Karsty，G.和Franceschi，R.T.(2000)J.Biol)。化学。275、4453-4459)。本研究探讨了成纤维细胞生长因子2对小鼠骨钙素基因在MC3T3-E1前成骨细胞中的调控机制。成纤维细胞生长因子-2以剂量和时间依赖的方式刺激MC3T3-E1前成骨细胞的骨钙素mRNA和启动子活性。在小鼠骨髓基质细胞中也得到了类似的结果。这种刺激需要Runx2及其在骨钙素启动子中的DNA结合部位。成纤维细胞生长因子-2还显著增加了细胞外信号调节激酶1和2(ERK1/2)的磷酸化，随后是Runx2的磷酸化。此外，特异性的ERK1/2磷酸化抑制剂U0126完全阻断了成纤维细胞生长因子-2刺激的Runx2的磷酸化。和骨钙素启动子活性，表明这种调控需要MAPK通路。缺失研究表明，Runx2的C-末端PST结构域是fgf-2反应所必需的。本研究首次证明了Runx2是通过MAPK途径被FGF2磷酸化并激活的，提示FGF2在调节Runx2功能和骨形成中起重要作用。
Fibroblast growth factor 2 (FGF-2) is an important regulator of bone formation and osteoblast activity. However, its mechanism of action on bone cells is largely unknown. A major route for FGF signaling is through the mitogen-activated protein kinase (MAPK) pathway. We showed recently that this pathway is important for activation and phosphorylation of Cbfa1/Runx2, an osteoblast-related transcription factor (Xiao, G., Jiang, D., Thomas, P., Benson, M. D., Guan, K., Karsenty, G., and Franceschi, R. T. (2000) J. Biol. Chem. 275, 4453-4459). The present study examined the mechanism of FGF-2 regulation of the mouse osteocalcin gene in MC3T3-E1 preosteoblastic cells. FGF-2 stimulated osteocalcin mRNA and promoter activity in a dose- and time-dependent manner in MC3T3-E1 preosteoblastic cells. Similar results were obtained in mouse bone marrow stromal cells. This stimulation required Runx2 and its DNA binding site in the osteocalcin promoter. FGF-2 also dramatically increased phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) followed by phosphorylation of Runx2. Furthermore, a specific ERK1/2 phosphorylation inhibitor, U0126, completely blocked both FGF-2-stimulated Runx2 phosphorylation. and osteocalcin promoter activity, indicating that this regulation requires the MAPK pathway. Deletion studies showed that the C-terminal PST domain of Runx2 is required for the FGF-2 response. This study is the first demonstration that Runx2 is phosphorylated and activated by FGF-2 via the MAPK pathway and suggests that FGF-2 plays an important role in regulation of Runx2 function and bone formation.