Hedgehog Activation Regulates Human Osteoblastogenesis
Hedgehog Activation Regulates Human Osteoblastogenesis
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DOI：
10.1016/j.stemcr.2020.05.008
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发表时间：
2020-07-14
影响因子：
5.9
通讯作者：
Ohba, Shinsuke
中科院分区：
文献类型：
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作者：
Onodera, Shoko;Saito, Akiko;Ohba, Shinsuke
两种遗传性疾病，戈林综合征和麦库恩-奥尔布赖特综合征(MAS)，在骨密度和刺猬(HH)活动方面表现出完全相反的症状。在这项研究中，我们利用基于人类诱导多能干细胞(IPSC)的这两种疾病的模型来了解HH信号在成骨中的作用。与同基因对照相比，Gorlin综合征来源的IPSCs在成骨培养中表现出成骨原生成和矿化的增加，HH信号的激活和一系列转录因子的上调。MAS特异性IPSCs在成骨培养中表现出低矿化和低HH信号活性；经HH信号激活的小分子处理后，受损的成骨细胞恢复到正常水平。这些数据表明，HH信号是成骨细胞与前体细胞分化的关键控制因素。这项研究可能为治疗由HH信号调节失调引起的钙化遗传异常铺平一条新的药物疗法。
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 osteoblastogen-esis 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.