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 (<i>ESR1</i>) 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 <i>Esr1</i> in PDGFRα (a fibroblast marker) + cells (<i>Esr1^ΔPα</i> ). Although muscle mass and grip strength were not different between groups, distal femoral BMD and cortical thickness were significantly lower in <i>Esr1^ΔPα</i> compared to control. Bone histomorphometry showed that cortical bone in <i>Esr1^ΔPα</i> exhibited a high turnover bone phenotype. Bulk RNA-seq using PDGFRα+ cells revealed that insulin-like growth factor-binding protein 5 (<i>Igfbp5</i>) expression was significantly higher in <i>Esr1^ΔPα</i> compared to control. Furthermore, serum IGFBP5 level was significantly higher in <i>Esr1^ΔPα</i> . IGFBP5 treatment in vitro significantly suppressed osteoblast differentiation and facilitated osteoclast differentiation. These results suggest that estrogen signaling in PDGFRα+ cells suppresses <i>Igfbp5</i> expression, then maintains bone mass, indicating that estrogen signaling in PDGFRα+ cells plays a significant role in bone metabolism.