Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification.
Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification.
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作者：
骨骼的形成在时间和空间上都受到精密的控制。异位骨化（HO）是骨骼外骨的病理形成，是创伤或遗传性疾病的常见并发症，可致残和致死。然而，潜在的分子机制在很大程度上是未知的。在这里，我们证明了Gαs通过抑制间充质祖细胞中的Hedgehog（Hh）信号传导来限制骨骼的骨形成。在进行性骨异型增生（POH）（一种由编码Gαs的GNAS无效突变引起的人类疾病）中，HH信号在异位成骨细胞和祖细胞中上调。异位Hh信号足以诱导HO，而Hh信号抑制在动物模型中阻断HO。由于我们先前的工作已经表明，GNAS功能突变的获得上调了纤维性发育不良（FD）中的WNT/β-Catenin信号传导，我们的研究结果将Gαs确定为成骨细胞分化的关键调节因子，通过维持两个关键信号传导通路之间的平衡：Wnt/β-catenin和Hh。为癌症治疗开发的HH信号传导抑制剂可以重新用于治疗HO和由GNAS失活引起的其他疾病。
Bone formation is exquisitely controlled in space and time. Heterotopic ossification (HO), the pathologic formation of extra-skeletal bone, occurs as a common complication of trauma or in genetic disorders and can be disabling and lethal. However, the underlying molecular mechanisms are largely unknown. Here we demonstrate that Gαs restricts bone formation to the skeleton by inhibiting Hedgehog (Hh) signaling in mesenchymal progenitor cells. In progressive osseous heteroplasia (POH), a human disease caused by null mutations in GNAS that encodes Gαs, HH signaling is upregulated in ectopic osteoblasts and progenitor cells. Ectopic Hh signaling is sufficient to induce HO, while Hh signaling inhibition blocks HO in animal models. As our previous work has shown that GNAS gain of function mutations upregulate WNT/β-Catenin signaling in fibrous dysplasia (FD), our findings identify Gαs as a critical regulator of osteoblast differentiation by maintaining a balance between two key signaling pathways: Wnt/β-catenin and Hh. HH signaling inhibitors developed for cancer therapy may be repurposed to treat HO and other diseases caused by GNAS inactivation.
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影响因子：
2.7
作者：
Joeng KS;Schumacher CA;Zylstra-Diegel CR;Long F;Williams BO
通讯作者：
Williams BO
影响因子：
15.8
作者：
Chen Y;Whetstone HC;Lin AC;Nadesan P;Wei Q;Poon R;Alman BA
通讯作者：
Alman BA
DOI：
10.1073/pnas.1006822107
发表时间：
2010-07-27
影响因子：
11.1
作者：
Kim, Jynho;Lee, John J.;Beachy, Philip A.
通讯作者：
Beachy, Philip A.
影响因子：
11.8
作者：
Jiang J;Hui CC
通讯作者：
Hui CC
影响因子：
11.8
作者：
Day, TF;Guo, XZ;Yang, YZ
通讯作者：
Yang, YZ