Hedgehog signaling in adult bone and cartilage homeostasis

Hedgehog （Hh）信号是发育和成人生理中细胞命运的重要调节因子。在骨骼系统中，软骨内骨形成过程中，Hh信号是间充质祖细胞向成骨细胞分化所必需的。此外，了解骨形成是如何在空间上受到严格控制也是非常重要的。然而，间充质祖细胞中的Hh信号是如何调控的以及骨形成是如何在空间上受到控制的，在很大程度上仍然是未知的。在过去的一年里，我们研究了异位骨化（HO）的潜在细胞和分子机制，异位骨化是一种由骨骼外骨形成引起的非常致残的疾病。我们从研究一种叫做进行性骨性异质增生（POH）的遗传形式开始。POH是由G蛋白偶联受体信号转导的Gas蛋白功能丧失引起的。我们已经建立了POH的动物模型，并通过体内和体外方法发现，在包括成人间充质祖细胞在内的多种组织中，Gas是Hh信号的重要调节剂。我们发现异位激活的Hh信号是引起HO的必要和充分条件。先前开发用于治疗癌症的Hh抑制剂可以重新用于预防HO。此外，我们采用遗传和生化相结合的方法研究了Gas和Hh信号在控制胚胎和成年动物间充质祖细胞成骨细胞分化中的功能和机制。

Hedgehog (Hh) signaling is an important regulator of cell fates in development and adult physiology. In the skeleton system, Hh signaling is required for the differentiation of mesenchymal progenitors into osteoblasts during endochondral bone formation. In addition, it is fundamentally important to understand how bone formation is tightly controlled spatially. However, how Hh signaling in mesenchymal progenitor cells is regulated and how bone formation is spatially controlled are still largely unknown. In the past year, we have investigated the underlying cellular and molecular mechanisms of heterotopic ossification (HO), a very disabling disease caused by extra-skeleton bone formation. We started by studying a genetic form of HO called progressive osseous heteroplasia (POH). POH is caused by loss of function in Gas protein, which transduces signaling from G protein coupled receptors. We have established animal models of POH and found with both in vivo and in vitro approaches that Gas is an important regulator of Hh signaling in multiple tissues including the adult mesenchymal progenitor cells. We found that ectopic activated Hh signaling is both necessary and sufficient for causing HO. Hh inhibitors previously developed to treat cancer can be repurposed to prevent HO. Furthermore, we investigated with combined genetic and biochemical approaches the function and mechanisms of Gas and Hh signaling in controlling osteoblast differentiation from mesenchymal progenitor cells in both embryos and adult animals.