Abstract
<title>Abstract</title> <p>Age-associated bone loss and osteoporosis disproportionately affect postmenopausal women and are commonly attributed to hormonal and metabolic alterations. However, the observation that women exhibit lower bone mass even prior to menopause suggests that additional non-hormonal mechanisms might contribute to the skeletal sexual dimorphism. Here, we identify sex-specific differences in fibroblast growth factor (FGF) signaling as a regulator of bone homeostasis. We show that the ligand FGF1 is markedly enriched in female bone stromal cells, whereas FGFRL1, a decoy receptor that attenuates FGF signaling, is highly expressed in males. An FGF1 gain-of-function approach in male mice increased bone marrow adiposity and reduced osteoblast-lineage cells, indicating a shift in mesenchymal lineage allocation toward adipogenesis. In contrast, pharmacological inhibition of FGF signaling or overexpression of recombinant FGFRL1 in females suppressed adipogenesis, increased osteoprogenitor abundance, and enhanced trabecular bone mass. Collectively, these findings establish sex-dependent FGF signaling as a critical determinant of skeletal homeostasis and suggest that modulation of this pathway may represent a therapeutic strategy for the treatment of bone loss associated with aging.</p>