Integrative Genetic and Single-Cell Analysis Reveals Macrophages as Key Mediators Linking Aging and Osteoporosis

Osteoporosis is a highly prevalent age-related disorder, and accumulating evidence suggests that it does not arise in isolation but is intrinsically linked to the aging process. Here, we employed integrative methods to systematically identify the relationship between aging and osteoporosis, and uncover the critical cell types and molecular regulators that mediate this association. Observational analysis of phenotypic data from UK Biobank and Mendelian Randomization analysis of summary-level statistics revealed that aging and osteoporosis are interrelated, acting as both causes and effects of each other. We identified macrophages as the key cell types mediating this association by integration of GWAS data with a comprehensively assembled single-cell transcriptomic atlas of bone remodeling. And the percentage of macrophages from bone marrow decreases with age. Additionally, shared genetic tools and weight co-expression network analysis were employed to uncover novel molecular regulators underlying this crosstalk. We identified TGFB1 and a novel gene, HNRNPUL1 , as key regulators that influence macrophages differentiation and function. In conclusion, our study provides observational and genetic evidence for a bidirectional relationship between aging and osteoporosis and unveils a macrophage-centric mechanism regulated by TGFB1 and HNRNPUL1 , offering new insights for age-related bone loss.