A Novel Mechanism of MSCs Responding to Occlusal Force for Bone Homeostasis

Abstract

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; Yap^f/f; Taz^f/f mice showed a decrease in CD31^hi 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 CD31^hiEmcn^hi endothelium and rescued the low bone mass phenotype of LepR-Cre; Yap^f/f; Taz^f/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.