Hedgehog signaling in adult bone and cartilage homeostasis

Hedgehog（Hh）信号是软骨内骨形成过程中间充质祖细胞分化成成骨细胞所必需的。然而，在成人骨稳态过程中，Hh信号在分化成骨细胞中的作用仍有待阐明。此外，Hh信号传导也是控制软骨细胞增殖和肥大所必需的。在过去的一年中，我们发现在出生后的骨骼中，随着成骨细胞的成熟，Hh信号活性逐渐降低。为了表征Hh信号在成人骨稳态中的功能，我们使用Cre-lox系统在成年小鼠的成熟成骨细胞中选择性地操纵Hh信号。通过去除Patched 1（Ptch 1）（Hh信号的负调节剂）上调Hh信号导致骨形成增加和过度骨吸收。因此，这些小鼠表现出严重的骨质减少。相反，通过灭活Smoothened（Smo）（一种Hh信号传导的正调节剂）来抑制成熟成骨细胞中的Hh信号传导，导致骨量增加，并防止衰老过程中的骨丢失。我们的研究结果表明，Hh信号是需要在成熟的成骨细胞调节骨形成和吸收和抑制Hh信号保护在正常过程中的老化骨丢失。我们还发现，Hh信号促进成人关节软骨细胞肥大，这表明激活的Hh信号可能是骨关节炎的危险因素。

Hedgehog (Hh) signaling is required for the differentiation of mesenchymal progenitors into osteoblasts during endochondral bone formation. However, the role of Hh signaling in differentiated osteoblasts during adult bone homeostasis remains to be elucidated. In addition, Hh signaling is also required to control chondrocyte proliferation and hypertrophy. In the past year we found that in the postnatal bone, Hh signaling activity was progressively reduced as osteoblasts mature. To characterize the function of Hh signaling in adult bone homeostasis, we have manipulated Hh signaling selectively in mature osteoblasts in adult mice using the Cre-lox system. Upregulation of Hh signaling by removing Patched 1 (Ptch1), a negative regulator of Hh signaling, leads to increased bone formaion and excessive bone resorption. As a consequence, these mice show severe osteopenia. Conversely, inhibition of Hh signaling in mature osteoblasts by inactivating Smoothened (Smo), a positive regulator of Hh signaling, resulted in increased bone mass and protection from bone loss during aging. Our results demonstrate that Hh signaling is required in mature osteoblasts to regulate both bone formation and resorption and inhibition of Hh signaling protects bone loss during the normal course of aging. We have also found that Hh signaling promotes chondrocyte hypertrophy in the adult joint, suggesting that activated Hh signaling maybe a risk factor for osteoarthritis.