Sex Steroid Hormone Regulation in Bone Metabolism

Bone is a dynamic tissue undergoing continual remodelling through tightly regulated cycles of formation by osteoblasts and resorption by osteoclasts. Sex steroid hormones such as oestrogens and androgens exert pivotal control over skeletal homeostasis at all life stages. Oestrogens, acting mainly through oestrogen receptor α, limit excessive resorption by suppressing RANKL expression in mesenchymal-derived lining cells and promote osteoblast survival, whereas androgens, via the androgen receptor, enhance bone mass by stimulating osteoblast proliferation and inhibiting osteoclast differentiation. Interplay with Wnt signalling, mechanical loading and systemic factors ensures adaptation of bone architecture to hormonal milieu, nutritional status and mechanical demands. Deficiency of sex steroids underlies the pathogenesis of postmenopausal osteoporosis, androgen-deficiency–related bone loss and altered fracture risk in gender-affirming therapy, prompting development of selective receptor modulators and targeted anabolic agents with global clinical implications.

Research from Nature Portfolio

Recent studies have elucidated key mechanisms by which oestrogen modulates bone resorption and formation. One investigation demonstrated that oestrogen receptor α in bone lining cells acts as a gatekeeper of resorption by suppressing expression of receptor activator of nuclear factor kappa-B ligand (RANKL), thereby limiting osteoclastogenesis and maintaining skeletal integrity in conditions of oestrogen sufficiency. Another pioneering work identified a neuroskeletal circuit in female mice whereby central oestrogen signalling in hypothalamic kisspeptin neurons adjusts peripheral bone mass; ablation of this pathway resulted in markedly enhanced trabecular and cortical density, revealing a brain-to-bone axis that fine-tunes mineral allocation according to energy demands.

Sex Steroid Hormone Regulation in Bone Metabolism publication trend

The graph below shows the total number of articles in sex steroid hormone regulation in bone metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

Osteoblast: a specialised cell that synthesises bone matrix and mediates mineralisation.

Osteoclast: a multinucleated cell responsible for bone resorption through acid and protease secretion.

RANKL: receptor activator of nuclear factor kappa-B ligand, a cytokine essential for osteoclast differentiation.

Estrogen receptor α (ERα): a nuclear transcription factor that binds 17β-oestradiol to regulate gene expression in bone cells.

Bone marrow stromal cell (BMSC): a multipotent progenitor capable of differentiating into osteoblasts, chondrocytes and adipocytes.

References

1. Estradiol increases cortical and trabecular bone accrual and bone strength in an adolescent male-to-female mouse model of gender-affirming hormone therapy. Bone Research (2024).
2. YAP/TEAD1 and β‐catenin/LEF1 synergistically induce estrogen receptor α to promote osteogenic differentiation of bone marrow stromal cells. MedComm (2023).
3. Estrogen Regulates Bone Turnover by Targeting RANKL Expression in Bone Lining Cells. Scientific Reports (2017).
4. Estrogen signaling in arcuate Kiss1 neurons suppresses a sex-dependent female circuit promoting dense strong bones. Nature Communications (2019).
5. Androgens and Androgen Receptor Actions on Bone Health and Disease: From Androgen Deficiency to Androgen Therapy. Cells (2019).