BMP canonical Smad signaling through Smad1 and Smad5 is required for endochondral bone formation.
BMP canonical Smad signaling through Smad1 and Smad5 is required for endochondral bone formation.
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DOI：
10.1242/dev.029926
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发表时间：
2009-04
期刊：
影响因子：
--
通讯作者：
Lyons KM
中科院分区：
文献类型：
--
作者：
Retting KN;Song B;Yoon BS;Lyons KM
骨形态发生蛋白（BMP）信号是软骨内骨形成所必需的。然而，bmp的作用是通过规范的Smad途径介导还是通过非规范的Smad途径介导尚不清楚。在这项研究中，我们确定了受体Smads 1、5和8在软骨形成中的作用。单个Smads的删除导致存活和可育的小鼠。然而，Smads 1、5和8的联合缺失会导致严重的软骨发育不良。Smad1/5CKO（软骨特异性敲除）突变小鼠与Smad1/5CKO几乎相同；Smad8-/-突变，表明smad1和5具有重叠的功能，并且在软骨中比Smad8更重要。Smad1/5CKO表型比Smad4CKO小鼠更严重，至少在软骨细胞中，这挑战了Smad4通过BMP途径介导Smad信号传导的教条。Smad1/5CKO小鼠的软骨发育不良伴随着BMP、FGF和Ihh/PTHrP信号通路间的相互作用失衡。我们发现Ihh是软骨细胞中BMP通路的直接靶点，FGF对Ihh的表达有拮抗作用。最后，我们测试了FGF是否通过Smad连接子磷酸化直接发挥其拮抗作用。结果支持另一种结论，即FGFs对BMP信号的影响在体内是间接的。
Bone morphogenetic protein (BMP) signaling is required for endochondral bone formation. However, whether or not the effects of BMPs are mediated via canonical Smad pathways or through noncanonical pathways is unknown. In this study we have determined the role of receptor Smads 1, 5 and 8 in chondrogenesis. Deletion of individual Smads results in viable and fertile mice. Combined loss of Smads 1, 5 and 8, however, results in severe chondrodysplasia. Smad1/5CKO (cartilage-specific knockout) mutant mice are nearly identical to Smad1/5CKO;Smad8-/- mutants, indicating that Smads 1 and 5 have overlapping functions and are more important than Smad8 in cartilage. The Smad1/5CKO phenotype is more severe than that of Smad4CKO mice, challenging the dogma, at least in chondrocytes, that Smad4 is required to mediate Smad signaling through BMP pathways. The chondrodysplasia in Smad1/5CKO mice is accompanied by imbalances in cross-talk between the BMP, FGF and Ihh/PTHrP pathways. We show that Ihh is a direct target of BMP pathways in chondrocytes, and that FGF exerts antagonistic effects on Ihh expression. Finally, we tested whether FGF exerts its antagonistic effects directly through Smad linker phosphorylation. The results support the alternative conclusion that the effects of FGFs on BMP signaling are indirect in vivo.
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