Multiscale analysis and functional validation of the cellular and genetic determinants of skeletal disease.

Summary

Using single-cell and cross-species genomics, the study maps 34 skeletal cell types, prioritizes disease-relevant populations via enrichment of rare disease and bone mineral density genes, and functionally validates targets in over 1,000 mouse models. It newly implicates endothelial and vascular smooth muscle cells in skeletal pathology and provides a framework to accelerate target discovery.

Key Findings

• Identified 34 distinct skeletal cell types, defining a critical endosteal compartment regulating bone turnover.
• Prioritized disease-relevant cells using enrichment for rare skeletal disorder genes and BMD-associated loci from extended UK Biobank GWAS.
• Functionally validated hundreds of candidates in over 1,000 genetically modified mouse models.
• Revealed endothelial and vascular smooth muscle cells as previously underappreciated skeletal-disease-relevant populations.

Clinical Implications

While preclinical, the atlas and validated gene sets prioritize targets (including vascular compartments) for osteoporosis and skeletal disorder drug development and may inform biomarker discovery.

Limitations

• Preclinical nature; translation from mouse to human pathophysiology may vary.
• Single-cell datasets and validations are focused on specific skeletal compartments and contexts.

Future Directions

Leverage the atlas to nominate and test vascular-targeted interventions in osteoporosis and integrate with longitudinal human imaging and serum biomarkers for clinical translation.