Sexually dimorphic estrogen sensing in skeletal stem cells controls skeletal regeneration

How bone-related sexually dimorphic traits are regulated hasn't been examined at the stem cell level. Here the authors show that skeletal stem cells (SSC), in female but not male mice, are directly controlled by estrogen signaling, which could be augmented to improve fracture repair. Sexually dimorphic tissues are formed by cells that are regulated by sex hormones. While a number of systemic hormones and transcription factors are known to regulate proliferation and differentiation of osteoblasts and osteoclasts, the mechanisms that determine sexually dimorphic differences in bone regeneration are unclear. To explore how sex hormones regulate bone regeneration, we compared bone fracture repair between adult male and female mice. We found that skeletal stem cell (SSC) mediated regeneration in female mice is dependent on estrogen signaling but SSCs from male mice do not exhibit similar estrogen responsiveness. Mechanistically, we found that estrogen acts directly on the SSC lineage in mice and humans by up-regulating multiple skeletogenic pathways and is necessary for the stem cell's ability to self- renew and differentiate. Our results also suggest a clinically applicable strategy to accelerate bone healing using localized estrogen hormone therapy.

Automated summary

This study investigates the regulation of bone-related sexually dimorphic traits at the stem cell level. The researchers find that estrogen signaling directly controls skeletal stem cells (SSCs) in female mice, but not in male mice. They also demonstrate that estrogen is necessary for the self-renewal and differentiation of SSCs, and suggest a potential clinical strategy for bone healing using localized estrogen hormone therapy.