TGFbeta2 mediates the effects of hedgehog on hypertrophic differentiation and PTHrP expression.
TGFbeta2 mediates the effects of hedgehog on hypertrophic differentiation and PTHrP expression.
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发表时间：
2002-04
期刊：
影响因子：
4.6
通讯作者：
J. Álvarez;P. Sohn;Xin Zeng;T. Doetschman;D. Robbins;R. Serra
中科院分区：
文献类型：
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作者：
J. Álvarez;P. Sohn;Xin Zeng;T. Doetschman;D. Robbins;R. Serra
软骨内骨的发育需要软骨雏形内几种细胞类型信号的协调。一个涉及印度刺猬（Ihh）和甲状旁腺激素相关肽（PTHrP）的信号级联已经被描述，其中肥大分化受到软骨细胞分泌的信号的限制，因为它们变得肥大。在这个负反馈循环中，Ihh通过调节Pthrp的表达来抑制肥厚分化，而Pthrp又直接作用于生长板中表达PTH/ Pthrp受体的软骨细胞。之前，我们已经证明PTHrP也在一个共同的信号级联中作用于转化生长因子β (tgfβ)的下游，以调节胚胎小鼠跖器官培养的肥厚分化。由于tgf β超家族的成员已被证明在几个发育系统中介导Hedgehog的作用，我们提出了一个模型，其中tgf β在一系列信号中作用于Ihh的下游和PTHrP的上游，从而调节生长板中的肥厚分化。本报告验证了tgfβ信号通路是Hedgehog基因对PTHRP肥厚分化和表达的影响所必需的假设：我们发现，Sonic Hedgehog基因（Shh）是Ihh的功能性替代品，可刺激器官培养的胚胎小鼠跖骨软骨膜中Tgfb2和Tgfb3 mRNA的表达，并且软骨膜中的tgfβ信号通路是抑制Shh对PTHRP表达的分化和调控所必需的。Shh的作用特别依赖于TGFbeta2，因为来自tgfb3缺失的胚胎的培养物对Shh有反应，而来自tgfb2缺失的胚胎的培养物对Shh没有反应。综上所述，这些数据表明TGFbeta2在调节软骨肥大分化过程中作为Ihh和PTHrP之间的信号中继。
The development of endochondral bones requires the coordination of signals from several cell types within the cartilage rudiment. A signaling cascade involving Indian hedgehog (Ihh) and parathyroid hormone related peptide (PTHrP) has been described in which hypertrophic differentiation is limited by a signal secreted from chondrocytes as they become committed to hypertrophy. In this negative-feedback loop, Ihh inhibits hypertrophic differentiation by regulating the expression of Pthrp, which in turn acts directly on chondrocytes in the growth plate that express the PTH/PTHrP receptor. Previously, we have shown that PTHrP also acts downstream of transforming growth factor beta (TGFbeta) in a common signaling cascade to regulate hypertrophic differentiation in embryonic mouse metatarsal organ cultures. As members of the TGFbeta superfamily have been shown to mediate the effects of Hedgehog in several developmental systems, we proposed a model where TGFbeta acts downstream of Ihh and upstream of PTHrP in a cascade of signals that regulate hypertrophic differentiation in the growth plate. This report tests the hypothesis that TGFbeta signaling is required for the effects of Hedgehog on hypertrophic differentiation and expression of PTHRP: We show that Sonic hedgehog (Shh), a functional substitute for Ihh, stimulates expression of Tgfb2 and Tgfb3 mRNA in the perichondrium of embryonic mouse metatarsal bones grown in organ cultures and that TGFbeta signaling in the perichondrium is required for inhibition of differentiation and regulation of Pthrp expression by Shh. The effects of Shh are specifically dependent on TGFbeta2, as cultures from Tgfb3-null embryos respond to Shh but cultures from Tgfb2-null embryos do not. Taken together, these data suggest that TGFbeta2 acts as a signal relay between Ihh and PTHrP in the regulation of cartilage hypertrophic differentiation.