Transforming Growth Factors β Coordinate Cartilage and Tendon Differentiation in the Developing Limb Mesenchyme
Transforming Growth Factors β Coordinate Cartilage and Tendon Differentiation in the Developing Limb Mesenchyme
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DOI：
10.1074/jbc.m109.014811
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发表时间：
2009-10-23
影响因子：
4.8
通讯作者：
Hurle, Juan M.
中科院分区：
文献类型：
--
作者：
Lorda-Diez, Carlos I.;Montero, Juan A.;Hurle, Juan M.
转化生长因子 β (TGF β) 信号传导作为修复软骨的潜在工具，越来越受到再生医学的关注，但该途径在发育系统中的软骨形成作用存在争议。在这里，我们分析了 TGF β 信号传导在体内和高密度微团培养物中发育肢体中胚层分化中的功能。在这些系统中，最高的信号传导活性与处于明显软骨细胞分化之前阶段的细胞相对应。有趣的是，TGFβ 的治疗将培养物的分化结果从软骨发生转变为纤维发生。这种表型重编程涉及通过 Smad 途径下调 Sox9 和聚集蛋白聚糖以及上调 Scleraxis 和 Tenomodulin。我们进一步表明，在体内实验模型系统中，TGF β 信号传导上调 Sox9，其中 TGF β 治疗诱导异位软骨形成。在寻找解释 TGF β 信号传导双重作用的线索时，我们发现 TGF β 似乎是软骨形成基因 Sox9 的直接诱导物，但 TGF β 信号传导转录抑制因子的存在调节了这一作用。我们确定 TGF 相互作用因子 Tgif1 和 SKI 样癌基因 SnoN 作为这种抑制功能的潜在候选者。 TGF beta 信号传导对 Tgif1 基因的调节与该途径的不同软骨形成和纤维形成作用相关，其在肢体中的表达模式标志着肌腱的发育。在功能实验中，我们发现 Tgif1 再现了 TGF beta 治疗的促纤维化作用。
Transforming growth factor beta (TGF beta) signaling has an increasing interest in regenerative medicine as a potential tool to repair cartilages, however the chondrogenic effect of this pathway in developing systems is controversial. Here we have analyzed the function of TGF beta signaling in the differentiation of the developing limb mesoderm in vivo and in high density micromass cultures. In these systems highest signaling activity corresponded with cells at stages preceding overt chondrocyte differentiation. Interestingly treatments with TGF beta s shifted the differentiation outcome of the cultures from chondrogenesis to fibrogenesis. This phenotypic reprogramming involved downregulation of Sox9 and Aggrecan and up-regulation of Scleraxis, and Tenomodulin through the Smad pathway. We further show that TGF beta signaling up-regulates Sox9 in the in vivo experimental model system in which TGF beta treatments induce ectopic chondrogenesis. Looking for clues explaining the dual role of TGF beta signaling, we found that TGF beta s appear to be direct inducers of the chondrogenic gene Sox9, but the existence of transcriptional repressors of TGF beta signaling modulates this role. We identified TGF-interacting factor Tgif1 and SKI-like oncogene SnoN as potential candidates for this inhibitory function. Tgif1 gene regulation by TGF beta signaling correlated with the differential chondrogenic and fibrogenic effects of this pathway, and its expression pattern in the limb marks the developing tendons. In functional experiments we found that Tgif1 reproduces the profibrogenic effect of TGF beta treatments.