Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein
Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein
复制标题
DOI：
10.1126/science.273.5275.613
复制
发表时间：
1996-08-02
期刊：
影响因子：
56.9
通讯作者：
Tabin, CJ
中科院分区：
文献类型：
--
作者：
Vortkamp, A;Lee, K;Tabin, CJ
软骨细胞分化的适当调控对于骨骼元件的形态发生是必要的，但对这一过程的分子调控知之甚少。印度刺猬（Ihh）的鸡同源物，是保守的hedgehog家族的一员，在骨形成过程中表达分泌蛋白，现已被分离出来。Ihh具有与Sonic hedgehog基因（Shh）相似的生物学特性，包括调节保守靶标patch （Ptc）和Gli的能力。Ihh在软骨元件的前增生性软骨细胞中表达，在那里它调节增生性分化的速度，Ihh的错误表达阻止增殖的软骨细胞启动增生性分化过程。Ihh信号的直接靶点是软骨膜，其中Gli和Ptc位于Ihh的表达域的侧面，Ihh诱导第二信号的表达，甲状旁腺激素相关蛋白（PTHrP），在关节周围软骨膜。对PTHrP（-/-）突变小鼠的分析表明，PTHrP蛋白向其在肥大前软骨细胞中的受体发出信号，从而阻断肥厚分化。将Hedgehog或PTHrP蛋白体外应用于正常或PTHrP（-/-）肢体外植体表明，PTHrP通过形成负反馈回路调节软骨细胞分化速率，从而介导Ihh的作用。
Proper regulation of chondrocyte differentiation is necessary for the morphogenesis of skeletal elements, yet little is known about the molecular regulation of this process, A chicken homolog of Indian hedgehog (Ihh), a member of the conserved Hedgehog family of secreted proteins that is expressed during bone formation, has now been isolated. Ihh has biological properties similar to those of Sonic hedgehog (Shh), including the ability to regulate the conserved targets Patched (Ptc) and Gli. Ihh is expressed in the prehypertrophic chondrocytes of cartilage elements, where it regulates the rate of hypertrophic differentiation, Misexpression of Ihh prevents proliferating chondrocytes from initiating the hypertrophic differentiation process, The direct target of Ihh signaling is the perichondrium, where Gli and Ptc flank the expression domain of Ihh, Ihh induces the expression of a second signal, parathyroid hormone-related protein (PTHrP), in the periarticular perichondrium, Analysis of PTHrP (-/-) mutant mice indicated that the PTHrP protein signals to its receptor in the prehypertrophic chondrocytes, thereby blocking hypertrophic differentiation, In vitro application of Hedgehog or PTHrP protein to normal or PTHrP (-/-) limb explants demonstrated that PTHrP mediates the effects of Ihh through the formation of a negative feedback loop that modulates the rate of chondrocyte differentiation.