Gli1 haploinsufficiency leads to decreased bone mass with an uncoupling of bone metabolism in adult mice.
Gli1 haploinsufficiency leads to decreased bone mass with an uncoupling of bone metabolism in adult mice.
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DOI：
10.1371/journal.pone.0109597
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Ohba S
中科院分区：
文献类型：
--
作者：
Kitaura Y;Hojo H;Komiyama Y;Takato T;Chung UI;Ohba S
Hedgehog（Hh）信号在多种发育过程中起着重要作用。这种信号传导是软骨内骨化过程中成骨细胞形成所必需的。与Hh信号在胚胎骨形成中的既定作用相反，其在成人骨稳态中的作用的证据并不完整。在这里，我们报告的参与Gli 1，Hh信号激活诱导的转录激活因子，在生理和病理条件下的出生后骨稳态。对Gli 1 +/−成年小鼠的骨骼肌分析显示，Gli 1单倍不足导致骨量减少，骨形成减少，骨吸收加速，表明骨代谢解偶联。Hh介导的成骨细胞分化在Gli 1 +/−前体培养物中受到很大程度的损害，并且通过腺病毒转导的Gli 1表达挽救了这种损害。此外，Gli 1 +/−前体显示出过早分化为骨细胞，并增加了支持破骨细胞生成的能力。当我们比较野生型和Gli 1 +/−成年小鼠之间的骨折愈合时，我们发现Gli 1 +/−小鼠表现出骨折愈合受损，软骨痂形成不足。这些数据表明，Gli 1，作用于Hh信号的下游，有助于成人骨代谢，其中该分子不仅促进成骨细胞分化，而且抑制成骨细胞向骨细胞成熟，以维持正常的骨稳态。
Hedgehog (Hh) signaling plays important roles in various development processes. This signaling is necessary for osteoblast formation during endochondral ossification. In contrast to the established roles of Hh signaling in embryonic bone formation, evidence of its roles in adult bone homeostasis is not complete. Here we report the involvement of Gli1, a transcriptional activator induced by Hh signaling activation, in postnatal bone homeostasis under physiological and pathological conditions. Skeletal analyses of Gli1 +/− adult mice revealed that Gli1 haploinsufficiency caused decreased bone mass with reduced bone formation and accelerated bone resorption, suggesting an uncoupling of bone metabolism. Hh-mediated osteoblast differentiation was largely impaired in cultures of Gli1 +/− precursors, and the impairment was rescued by Gli1 expression via adenoviral transduction. In addition, Gli1 +/− precursors showed premature differentiation into osteocytes and increased ability to support osteoclastogenesis. When we compared fracture healing between wild-type and Gli1 +/− adult mice, we found that the Gli1 +/− mice exhibited impaired fracture healing with insufficient soft callus formation. These data suggest that Gli1, acting downstream of Hh signaling, contributes to adult bone metabolism, in which this molecule not only promotes osteoblast differentiation but also represses osteoblast maturation toward osteocytes to maintain normal bone homeostasis.
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影响因子：
3.7
作者：
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通讯作者：
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通讯作者：
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