Identification and Mechanisms of Osteocyte Subsets Involved in the Pathological Progression of Osteoporosis

Abstract Osteocytes are the most abundant cell type in bone. However, the detailed functions of osteocyte subsets in osteoporosis have remained obscure. In this study, it is aimed to investigate the impact of osteocyte subset heterogeneity on the pathological process of osteoporosis and new potential molecular mechanisms. Six osteocyte subsets are identified in mouse bones by single‐cell sequencing. Among them, the epidermal growth factor receptor (Egfr)+ interleukin‐1 receptor type I (Il1r1)+ Semaphorin 5a (Sema5a)+osteocyte subpopulation (bone homeostasis regulatory osteocytes, BHR‐Ocys) played a key role in the maintenance of bone homeostasis by regulating osteoblasts and osteoclasts. The data confirm that the increased proportion of BHR‐Ocys contributes to bone loss in the postmenopausal osteoporotic mice. Mechanistically, Sema5a derived from BHR‐Ocys binds to the osteoclast receptor protein Plexin A1 (Plxna1), thereby activating the phosphatidylinositol‐3 kinase/protein kinase B/myelocytomatosis oncogen (PI3K/AKT/Myc) signaling pathway, leading to active osteoclast‐mediated bone resorption. In conclusion, BHR‐Ocys is a key cell subpopulation in the regulation of bone homeostasis. The Sema5a‐Plxna1 axis is an important mechanism for BHR‐Ocys to regulate osteoclast differentiation. The study provides new insights into the role and mechanism of osteocytes in the regulation of bone homeostasis and identifies new targets for the prevention and treatment of osteoporosis.