Estrogen signaling in PDGFRα+ cells positively regulates cortical bone metabolism via IGFBP5 in female mice.

The prevalence of both osteoporosis and sarcopenia increases with age and about 60% of elderly sarcopenia patients also develop osteoporosis. However, the co-occurrence of osteoporosis and sarcopenia remains unclear. We performed single-cell 5' RNA-seq on human skeletal muscle tissues and investigated the enrichment of heritability for musculoskeletal traits in cell type specific cis-regulatory regions. We found the fibroblast-specific cis-regulatory regions are highly enriched in the heritability of bone mineral density (BMD). Using genome-wide association study, we identified estrogen receptor α (ESR1) as a common transcription factor that correlated with both BMD and lean mass. We hypothesized that deficiency of estrogen signaling in fibroblast may attenuate musculoskeletal homeostasis. Therefore, we generated mice lacking Esr1 in PDGFRα (a fibroblast marker) + cells (Esr1(ΔPα) ). Although muscle mass and grip strength were not different between groups, distal femoral BMD and cortical thickness were significantly lower in Esr1(ΔPα) compared to control. Bone histomorphometry showed that cortical bone in Esr1(ΔPα) exhibited a high turnover bone phenotype. Bulk RNA-seq using PDGFRα+ cells revealed that insulin-like growth factor-binding protein 5 (Igfbp5) expression was significantly higher in Esr1(ΔPα) compared to control. Furthermore, serum IGFBP5 level was significantly higher in Esr1(ΔPα) . IGFBP5 treatment in vitro significantly suppressed osteoblast differentiation and facilitated osteoclast differentiation. These results suggest that estrogen signaling in PDGFRα+ cells suppresses Igfbp5 expression, then maintains bone mass, indicating that estrogen signaling in PDGFRα+ cells plays a significant role in bone metabolism.