Smad6 is essential to limit BMP signaling during cartilage development.
Smad6 is essential to limit BMP signaling during cartilage development.
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DOI：
10.1002/jbmr.443
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发表时间：
2011-10
影响因子：
6.2
通讯作者：
Lyons, Karen M.
中科院分区：
文献类型：
--
作者：
Estrada, Kristine D.;Retting, Kelsey N.;Chin, Alana M.;Lyons, Karen M.
骨形态发生蛋白（BMP）信号通路调节软骨内骨形成的多个方面。已经确定了细胞外拮抗剂作为BMP信号传导调节剂的重要性。体外研究表明，细胞内调节剂，抑制性Smads 6和7，可以调节BMP介导的软骨细胞的作用。虽然在体内的研究，其中抑制性Smads在软骨中过表达的抑制性Smads有可能限制BMP信号在体内，抑制性Smad活性在骨骼组织中的生理相关性是未知的。在这项研究中，我们确定了Smad 6在软骨内骨形成中的作用。Smad 6基因缺失导致小鼠中轴骨和无中轴骨发育缺陷。具体而言，Smad 6 −/−小鼠表现出第七颈椎的后向转化，腰椎的双侧骨化中心，以及由于胸骨带融合不完全而导致的双胸骨节。无骨的组织学分析显示Smad 6 −/−小鼠在妊娠中期肥大分化和矿化的延迟发生。然而，到妊娠晚期，一个扩大的肥大区，与增加池的增殖细胞进行肥大，是明显的Smad 6突变生长板。突变体表型至少部分归因于Smad 6缺陷型软骨细胞中BMP反应性增加。总的来说，我们的研究结果表明，Smad 6是必要的，以限制BMP信号在软骨内骨形成。
Bone morphogenetic protein (BMP) signaling pathways regulate multiple aspects of endochondral bone formation. The importance of extracellular antagonists as regulators of BMP signaling has been defined. In vitro studies reveal that the intracellular regulators, inhibitory Smads 6 and 7, can regulate BMP-mediated effects on chondrocytes. Although in vivo studies in which inhibitory Smads were overexpressed in cartilage have shown that inhibitory Smads have the potential to limit BMP signaling in vivo, the physiological relevance of inhibitory Smad activity in skeletal tissues is unknown. In this study, we have determined the role of Smad6 in endochondral bone formation. Loss of Smad6 in mice leads to defects in both axial and appendicular skeletal development. Specifically, Smad6−/− mice exhibit a posterior transformation of the seventh cervical vertebra, bilateral ossification centers in lumbar vertebrae, and bifid sternebrae due to incomplete sternal band fusion. Histological analysis of appendicular bones revealed delayed onset of hypertrophic differentiation and mineralization at midgestation in Smad6−/− mice. By late gestation, however, an expanded hypertrophic zone, associated with an increased pool of proliferating cells undergoing hypertrophy, was evident in Smad6 mutant growth plates. The mutant phenotype is attributed, at least in part, to increased BMP responsiveness in Smad6-deficient chondrocytes. Overall, our results show that Smad6 is required to limit BMP signaling during endochondral bone formation.
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DOI：
10.1083/jcb.200106023
发表时间：
2001-12-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hanyu A;Ishidou Y;Ebisawa T;Shimanuki T;Imamura T;Miyazono K
通讯作者：
Miyazono K
DOI：
10.1073/pnas.0503617102
发表时间：
2005-12-13
影响因子：
11.1
作者：
Kobayashi, T;Lyons, KM;Kronenberg, HM
通讯作者：
Kronenberg, HM
影响因子：
5.3
作者：
Benchabane, H;Wrana, JL
通讯作者：
Wrana, JL
影响因子：
64.8
作者：
Imamura, T;Takase, M;Miyazono, K
通讯作者：
Miyazono, K
影响因子：
2.6
作者：
Duprez, D;Bella, EJD;FrancisWest, PH
通讯作者：
FrancisWest, PH