Signal transductions induced by bone morphogenetic protein-2 and transforming growth factor-β in normal human osteoblastic cells
Signal transductions induced by bone morphogenetic protein-2 and transforming growth factor-β in normal human osteoblastic cells
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DOI：
10.1074/jbc.m200794200
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发表时间：
2002-05-03
影响因子：
4.8
通讯作者：
Cheng, SL
中科院分区：
文献类型：
--
作者：
Lai, CF;Cheng, SL
转化生长因子β（TGF-β）在许多细胞类型中激活Ras/MAPK信号传导。由于TGF-β和BMP-2发挥类似的作用，我们检查了这种信号是否受到这两种因素的刺激，并分析了这种信号与成骨细胞中Smads之间的关系。BMP-2和TGF-β刺激Ras、MAPK和AP-1活性。c-Fos、FosB/DeltaFosB、Fra-1、Fra-2和JunB的DNA结合活性上调，而JunD活性降低。c-Fos、FosB/DeltaFosB和JunB与Smad 4相关。BMP-2和TGF-β对AP-1的刺激依赖于Smad信号，抗Smad 4抗体干扰AP-1活性。因此，BMP-2和TGF-β激活成骨细胞中的Ras/MAPK/AP-1和Smad信号传导，其中Smad调节AP-1活性。为了确定MAPK在BMP-2和TGF-β功能中的作用，我们分析了ERK和p38抑制剂对骨基质蛋白表达和JunB和JunD水平的调节作用。ERK和p38介导TGF-β抑制骨钙素和JunD以及刺激JunB。p38在BMP-2上调I型胶原、纤连蛋白、骨桥蛋白、骨钙蛋白和碱性磷酸酶活性中是必需的，而ERK介导BMP-2刺激纤连蛋白和骨桥蛋白。因此，ERK和p38差异介导成骨细胞中TGF-β和BMP-2的功能。
Transforming growth factor beta (TGF-beta) activates Ras/MAPK signaling in many cell types. Because TGF-beta and BMP-2 exert similar effects, we examined if this signaling is stimulated by both factors and analyzed the relationship between this signaling and the Smads in osteoblasts. BMP-2 and TGF-beta stimulated Ras, MAPK, and AP-1 activities. The DNA binding activities of c-Fos, FosB/DeltaFosB, Fra-1, Fra-2, and JunB were up-regulated whereas JunD activity was decreased. c-Fos, FosB/DeltaFosB, and JunB were associated with Smad4. The stimulation of AP-1 by BMP-2 and TGF-beta was dependent on Smad signaling, and anti-Smad4 antibody interfered with AP-1 activity. Thus, BMP-2 and TGF-beta activate both Ras/MAPK/AP-1 and Smad signaling in osteoblasts with Smads modulating AP-1 activity. To determine the roles of MAPK in BMP-2 and TGF-beta function, we analyzed the effect of ERK and p38 inhibitors on the regulation of bone matrix protein expression and JunB and JunD levels by these two factors. ERK and p38 mediated TGF-beta suppression of osteocalcin and JunD as well as stimulation of JunB. p38 was essential in BMP-2 upregulation of type I collagen, fibronectin, osteopontin, osteocalcin, and alkaline phosphatase activity whereas ERK mediated BMP-2 stimulation of fibronectin and osteopontin. Thus, ERK and p38 differentially mediate TGF-beta and BMP-2 function in osteoblasts.