Bone Mass and Osteoblast Activity Are Sex-Dependent in Mice Lacking the Estrogen Receptor alpha in Chondrocytes and Osteoblast Progenitor Cells (vol 23, 2902, 2022)

While estrogen receptor alpha (ER alpha) is known to be important for bone development and homeostasis, its exact function during osteoblast differentiation remains unclear. Conditional deletion of ER alpha during specific stages of osteoblast differentiation revealed different bone phenotypes, which were also shown to be sex-dependent. Since hypertrophic chondrocytes can transdifferentiate into osteoblasts and substantially contribute to long-bone development, we aimed to investigate the effects of ER alpha deletion in both osteoblast and chondrocytes on bone development and structure. Therefore, we generated mice in which the ER alpha gene was inactivated via a Runx2-driven cyclic recombinase (ER alpha(fl/fl;) (Runx2Cre)). We analyzed the bones of 3-month-old ER alpha(fl/fl;) (Runx2Cre) mice by biomechanical testing, micro-computed tomography, and cellular parameters by histology. Male ER alpha(fl/fl;) (Runx2Cre) mice displayed a significantly increased cortical bone mass and flexural rigidity of the femurs compared to age-matched controls with no active Cre-transgene (ER alpha(fl/fl)). By contrast, female ER alpha(fl/fl;) (Runx2Cre) mice exhibited significant trabecular bone loss, whereas in cortical bone periosteal and endosteal diameters were reduced. Our results indicate that the ER alpha in osteoblast progenitors and hypertrophic chondrocytes differentially contributes to bone mass regulation in male and female mice and improves our understanding of ER alpha signaling in bone cells in vivo.