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Development of bone-active therapies has been hindered by limited understanding of the cells and genes that regulate the skeleton. We exploited the value of cross-species analysis and developed single-cell methodologies in skeletal tissues to define the critical endosteal compartment that regulates bone turnover. Thirty-four distinct cell types were identified, and disease-relevant cells prioritized using enrichment for rare skeletal disorder genes and bone-mineral-density-associated genes in an extended UK Biobank genome-wide association study. Functional validation was undertaken in over 1,000 genetically modified mouse models. Endothelial cells and vascular smooth muscle cells were identified as new skeletal-disease-relevant cells alongside osteoblast, chondrocyte and osteoclast cell lineages. Hundreds of cell-specific genes with unappreciated roles in skeletal pathophysiology were identified. 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L.R-M., A.V-Z., R.E.McIntyre, E.M.H. and J.P.T-K. are receiving or have received compensation from Relation Therapeutics. E.M.H. is a trustee of the Kennedy Trust (London). S.E.Y. is founder and director of Compbiosphere, a computational biology analytics and consulting company. R.D.B. is on the advisory board of Amgen, consults for Guidepoint Advisors and receives editorial stipends from Elsevier, The Endocrine Society and Wolters Kluwer. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}