Hedgehog signaling in adult bone and cartilage homeostasis

Hedgehog(HH)信号是软骨内成骨过程中间充质祖细胞分化为成骨细胞所必需的。然而，HH信号在成骨细胞分化过程中的作用仍有待阐明。此外，HH信号也是控制软骨细胞增殖和肥大所必需的。在过去的一年里，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信号在成年骨内稳态中的作用，我们使用Cre-lox系统选择性地在成年小鼠的成骨细胞中操纵HH信号。通过去除HH信号的负调控因子Patch1(Ptch1)上调HH信号，会导致骨形成增加和过度的骨吸收。结果，这些小鼠表现出严重的骨量减少。相反，通过失活HH信号的正向调节因子Smoothens(Smo)来抑制成熟成骨细胞中的HH信号，会导致骨量增加，并防止衰老过程中的骨丢失。我们的结果表明，成熟的成骨细胞需要HH信号来调节骨形成和骨吸收，抑制HH信号可以保护正常衰老过程中的骨丢失。我们还发现，HH信号促进了成人关节软骨细胞的肥大，提示激活的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.