Multiscale analysis and functional validation of the cellular and genetic determinants of skeletal disease
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
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.
Date Issued
2026-07-01
Date Acceptance
2026-05-15
Citation
Nature Genetics, 2026, 58 (7), pp.1530-1545
ISSN
1061-4036
Publisher
Springer Science and Business Media LLC
Start Page
1530
End Page
1545
Journal / Book Title
Nature Genetics
Volume
58
Issue
7
Copyright Statement
© The Author(s) 2026 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/42432248
PII: 10.1038/s41588-026-02640-9
Subjects
International Federation of Musculoskeletal Research Societies (IFMRS) Big Data Working Group
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2026-07-10