Two genetic diseases, Gorlin syndrome and McCune-Albright syndrome (MAS), show completely opposite symptoms in terms of bone mineral density and hedgehog (Hh) activity. In this study, we utilized human induced pluripotent stem cell (iPSC)-based models of the two diseases to understand the roles of Hh signaling in osteogenesis. Gorlin syndrome-derived iPSCs showed increased osteoblastogenesis and mineralization with Hh signaling activation and upregulation of a set of transcription factors in an osteogenic culture, compared with the isogenic control. MAS-specific iPSCs showed poor mineralization with low Hh signaling activity in the osteogenic culture; impaired osteoblastogenesis was restored to the normal level by treatment with an Hh signaling-activating small molecule. These data suggest that Hh signaling is a key controller for differentiation of osteoblasts from precursors. This study may pave a path to new drug therapies for genetic abnormalities in calcification caused by dysregulation of Hh signaling.

就骨矿物质密度和刺猬（Hh）活性而言，两种遗传疾病，高林综合症和麦昆-奥尔布赖特综合症（MAS），表现出完全相反的症状。在这项研究中，我们利用人类诱导的多能干细胞（iPSC）为基础的两种疾病模型，以了解Hh信号在成骨中的作用。与同基因对照相比，源自Gorlin综合征的iPSCs通过Hh信号激活和成骨培养物中一组转录因子的上调显示成骨细胞生成和矿化增加。MAS特异的iPSC在成骨培养物中显示出较差的矿化度和低Hh信号传导活性。通过用Hh信号激活小分子治疗，受损的成骨细胞可以恢复到正常水平。这些数据表明，Hh信号传导是成骨细胞与前体细胞分化的关键控制器。这项研究可能为因Hh信号异常调节引起的钙化基因异常的新药物疗法铺平道路。