BMP-IHH-mediated interplay between mesenchymal stem cells and osteoclasts supports calvarial bone homeostasis and repair.
BMP-IHH-mediated interplay between mesenchymal stem cells and osteoclasts supports calvarial bone homeostasis and repair.
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BMP-IHH介导的间充质干细胞和破骨细胞之间的相互作用支持钙质骨稳态和修复。
DOI：
10.1038/s41413-018-0031-x
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发表时间：
2018
期刊：
影响因子：
12.7
通讯作者：
Chai Y
中科院分区：
文献类型：
--
作者：
Guo Y;Yuan Y;Wu L;Ho TV;Jing J;Sugii H;Li J;Han X;Feng J;Guo C;Chai Y
颅骨由纤维缝线连接。这些缝线提供了一个利基环境，其中包括间充质干细胞(MSCs)、成骨细胞和破骨细胞，有助于维持颅骨的动态平衡和修复。颅缝内的成骨细胞功能异常或MSCs减少可导致颅骨缺失，如颅骨融合。尽管这些细胞类型中的每一种在颅缝中都具有重要的功能，但我们对它们之间的串扰在调节颅骨内稳态和损伤修复中所起的作用知之甚少。在这里，我们发现缝合间充质干细胞可以诱导出显示活跃的骨形态发生蛋白(BMP)信号的成骨前体细胞，并依赖于BMP介导的印度刺猬(IHH)信号来平衡成骨和破骨细胞的活性。IHH信号和核因子kappa受体激活剂Β配体(RANKL)可能协同作用促进破骨细胞的分化和吸收活性。MSCs中BMPR1A的缺失导致刺猬(HH)信号的下调和颅缝的减少。值得注意的是，HH信号的激活部分恢复了BMPR1A突变小鼠的缝合形态，表明BMP介导的HH信号在调节缝合组织动态平衡方面的功能重要性。此外，BMPR1A突变小鼠的CD200+细胞数量增加，这也可能是突变小鼠骨缝中破骨细胞活性受到抑制的原因之一。最后，缝合间充质干细胞在修复颅骨损伤后的骨缺损过程中需要BMP介导的HH信号。总之，我们的研究揭示了调节颅缝内细胞-细胞相互作用的分子和细胞机制，该机制调节颅骨的动态平衡和修复。了解调节颅缝细胞的信号机制有助于制定修复颅骨缺损或骨折的策略。颅缝中的成骨细胞、破骨细胞和间充质干细胞(MSCs)如何调节颅骨的内环境平衡和修复，目前还知之甚少。美国南加州大学的Yang Chai及其同事表示，阻止骨髓间充质干细胞中骨形态发生蛋白受体IA(BMPR1A)的表达会导致颅缝缺陷，在这些缺陷中，成骨活性增加，破骨细胞活性降低。刺激Hedgehog信号通路不仅部分挽救了BMPR1A突变小鼠的缺损缝，而且促进了损伤后的颅骨愈合，突显了BMP介导的Hedgehog信号在平衡颅骨形成和吸收方面的重要性。
Calvarial bones are connected by fibrous sutures. These sutures provide a niche environment that includes mesenchymal stem cells (MSCs), osteoblasts, and osteoclasts, which help maintain calvarial bone homeostasis and repair. Abnormal function of osteogenic cells or diminished MSCs within the cranial suture can lead to skull defects, such as craniosynostosis. Despite the important function of each of these cell types within the cranial suture, we have limited knowledge about the role that crosstalk between them may play in regulating calvarial bone homeostasis and injury repair. Here we show that suture MSCs give rise to osteoprogenitors that show active bone morphogenetic protein (BMP) signalling and depend on BMP-mediated Indian hedgehog (IHH) signalling to balance osteogenesis and osteoclastogenesis activity. IHH signalling and receptor activator of nuclear factor kappa-Β ligand (RANKL) may function synergistically to promote the differentiation and resorption activity of osteoclasts. Loss of Bmpr1a in MSCs leads to downregulation of hedgehog (Hh) signalling and diminished cranial sutures. Significantly, activation of Hh signalling partially restores suture morphology in Bmpr1a mutant mice, suggesting the functional importance of BMP-mediated Hh signalling in regulating suture tissue homeostasis. Furthermore, there is an increased number of CD200+ cells in Bmpr1a mutant mice, which may also contribute to the inhibited osteoclast activity in the sutures of mutant mice. Finally, suture MSCs require BMP-mediated Hh signalling during the repair of calvarial bone defects after injury. Collectively, our studies reveal the molecular and cellular mechanisms governing cell–cell interactions within the cranial suture that regulate calvarial bone homeostasis and repair. Understanding the signaling mechanisms regulating cells in cranial sutures could help develop strategies for repairing skull defects or fractures. Little is known about how osteoblasts, osteoclasts and mesenchymal stem cells (MSCs) in cranial sutures regulate the homeostasis and repair of skull bones. Yang Chai at the University of Southern California, United States, and colleagues show that preventing the expression of bone morphogenetic protein receptor type IA (Bmpr1a) in MSCs leads to defective cranial sutures in which osteogenic activity is increased and osteoclast activity is reduced. Stimulating the Hedgehog signaling pathway not only partially rescued the defective sutures but also promoted skull bone healing after injury in Bmpr1a mutant mice, highlighting the importance of BMP-mediated Hedgehog signaling for balancing skull bone formation and resorption.
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