Michael R. G. Dack

Musculoskeletal diseases are a major health burden. 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. This comprehensive cellular and molecular framework underpins skeletal physiology and disease and will help prioritize new therapeutic targets to accelerate development of therapies to treat musculoskeletal disease.