| Title: | Multiscale analysis and functional validation of the cellular and genetic determinants of skeletal disease |
| Journal: | Nature Genetics |
| Published: | 10 Jul 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42432248/ |
| DOI: | https://doi.org/10.1038/s41588-026-02640-9 |
Publication 20314
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
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.</p>
13 Keywords
- Animals
- Bone Density
- Bone Diseases
- Bone and Bones
- Chondrocytes
- Disease Models, Animal
- Endothelial Cells
- Genome-Wide Association Study
- Humans
- Mice
- Osteoblasts
- Osteoclasts
- Single-Cell Analysis
50 Authors
- Ryan C. Chai
- Mischa Lundberg
- Bernard Freudenthal
- James T. Smith
- Andrew P. Boughton
- Yuandan Zhang
- Kaitlyn A. Flynn
- Monika Frysz
- Alexander P. Corr
- Weng Hua Khoo
- Davide Komla-Ebri
- Michael R. G. Dack
- Siobhan E. Guilfoyle
- John G. Logan
- Natalie C. Butterfield
- Victoria D. Leitch
- Andrea S. Pollard
- Riikka E. Mäkitie
- Nathaniel Bradford
- Lorenzo Ramos-Mucci
- Amaia Vilas-Zornoza
- Yunshun Chen
- Raymond K. H. Yip
- Jeremy Er
- Siew Zhuan Tan
- Michelle M. McDonald
- Scott E. Youlten
- C. Marcelo Sergio
- Ariel Castro-Martinez
- Shelley G. Young
- Elena Skorokhodova
- David M. Evans
- Joseph E. Powell
- Christiaan A. de Leeuw
- Adam D. Ewing
- John A. Eisman
- Robert D. Blank
- Tri Giang Phan
- Anne K. Lagendijk
- Edwin D. Hawkins
- Horng Lii Oh
- Rebecca E. McIntyre
- Edith M. Hessel
- Jake P. Taylor-King
- Paul A. Baldock
- Emma L. Duncan
- Graham R. Williams
- J. H. Duncan Bassett
- Peter I. Croucher
- John P. Kemp
1 Application
| Application ID | Title |
|---|---|
| 53641 | Determining the genetic and environmental aetiology of complex traits and diseases using existing and novel statistical methodologies |
Enabling scientific discoveries that improve human health