Alveolar bone, as tooth-supporting bone for mastication, is sensitive to occlusal force. However, the mechanism of alveolar bone loss after losing occlusal force remains unclear. Here, we performed single-cell RNA sequencing of nonhematopoietic (CD45–) cells in mouse alveolar bone after removing the occlusal force. Mesenchymal stromal cells (MSCs) and endothelial cell (EC) subsets were significantly decreased in frequency, as confirmed by immunofluorescence and flow cytometry. The osteogenic and proangiogenic abilities of MSCs were impaired, and the expression of mechanotransducers yes associated protein 1 ( Yap) and WW domain containing transcription regulator 1 ( Taz) in MSCs decreased. Conditional deletion of Yap and Taz from LepR+ cells, which are enriched in MSCs that are important for adult bone homeostasis, significantly decreased alveolar bone mass and resisted any further changes in bone mass induced by occlusal force changes. Interestingly, LepR-Cre; Yapf/f; Tazf/f mice showed a decrease in CD31hi endomucin (Emcn)hi endothelium, and the expression of some EC-derived signals acting on osteoblastic cells was inhibited in alveolar bone. Mechanistically, conditional deletion of Yap and Taz in LepR+ cells inhibited the secretion of pleiotrophin (Ptn), which impaired the proangiogenic capacity of LepR+ cells. Knockdown in MSC-derived Ptn repressed human umbilical vein EC tube formation in vitro. More important, administration of recombinant PTN locally recovered the frequency of CD31hiEmcnhi endothelium and rescued the low bone mass phenotype of LepR-Cre; Yapf/f; Tazf/f mice. Taken together, these findings suggest that occlusal force governs MSC-regulated endothelium to maintain alveolar bone homeostasis through the Yap/Taz/Ptn axis, providing a reference for further understanding of the relationship between dysfunction and bone homeostasis.

中文翻译：

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间充质干细胞响应咬合力维持骨稳态的新机制


牙槽骨作为咀嚼时的牙齿支撑骨，对咬合力敏感。然而，失去咬合力后牙槽骨丢失的机制仍不清楚。在这里，我们在消除咬合力后对小鼠牙槽骨中的非造血 (CD45–) 细胞进行了单细胞 RNA 测序。免疫荧光和流式细胞术证实，间充质基质细胞（MSC）和内皮细胞（EC）亚群的频率显着降低。 MSCs的成骨和促血管生成能力受损，MSCs中机械转导器yes相关蛋白1（Yap）和含有WW结构域的转录调节因子1（Taz）的表达减少。 LepR+细胞富含对成人骨稳态很重要的间充质干细胞，有条件地删除Yap和Taz会显着降低牙槽骨量，并抵抗咬合力变化引起的骨量进一步变化。有趣的是，LepR-Cre；叶夫/f； Tazf/f小鼠表现出内皮细胞CD31hi内粘蛋白(Emcn)hi减少，并且牙槽骨中一些作用于成骨细胞的EC衍生信号的表达受到抑制。从机制上讲，LepR+细胞中Yap和Taz的条件性缺失抑制了多效素（Ptn）的分泌，从而损害了LepR+细胞的促血管生成能力。 MSC 衍生的 Ptn 的敲低可抑制体外人脐静脉 EC 管的形成。更重要的是，重组PTN的施用局部恢复了CD31hiEmcnhi内皮的频率并挽救了LepR-Cre的低骨量表型；叶夫/f； Tazf/f 小鼠。 综上所述，这些研究结果表明咬合力通过Yap/Taz/Ptn轴控制MSC调节的内皮细胞维持牙槽骨稳态，为进一步理解功能障碍与骨稳态之间的关系提供参考。