Abstract
While estrogen receptor alpha (ERα) is known to be important for bone development and homeostasis, its exact function during osteoblast differentiation remains unclear. Conditional deletion of ERα 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 ERα deletion in both osteoblast and chondrocytes on bone development and structure. Therefore, we generated mice in which the ERα gene was inactivated via a Runx2-driven cyclic recombinase (ERαfl/fl; Runx2Cre). We analyzed the bones of 3-month-old ERαfl/fl; Runx2Cre mice by biomechanical testing, micro-computed tomography, and cellular parameters by histology. Male ERαfl/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 (ERαfl/fl). By contrast, female ERαfl/fl; Runx2Cre mice exhibited significant trabecular bone loss, whereas in cortical bone periosteal and endosteal diameters were reduced. Our results indicate that the ERα in osteoblast progenitors and hypertrophic chondrocytes differentially contributes to bone mass regulation in male and female mice and improves our understanding of ERα signaling in bone cells in vivo.
Highlights
Sex steroids are essential for skeletal development and regulate bone mass in both males and females [1]
We aimed to examine whether ERα signaling in osteoblast lineage-specific cells and hypertrophic chondrocytes are required for bone formation and development
The Runx2-Cre model allows to study the role of ERα in osteoblast progenitor cells directly derived from skeletal stem cells, and in hypertrophic chondrocytes eventually transdifferentiating into osteoblasts during long bone development
Summary
Sex steroids are essential for skeletal development and regulate bone mass in both males and females [1]. The effects of estrogen on bone are mainly mediated via the two estrogen receptors (ERs), ERα and ERβ, which can both be activated by androgens after aromatization into estrogens [6,7]. ERα has become a major focus of research, since a human case report demonstrated that a point mutation in its gene resulted in osteoporosis and unfused growth plates in a 28-year-old man [14]. Case reports from men showed that during bone healing, ERα expression is lower in in hypertrophic chondrocytes, shown by imm gene expression analysis of the fractured femurs [21]. Furth ported that cultured human osteoblasts from men and wome gen or ERα/ERβ-specific agonists in a sex-specific manner [22 that suffer from an aromatase deficiency together with preclinical studies demonstrated the expression levels of ERα/ERβ as well as their response to the importance of estrogens for male skeletal homeostasis [15–18]. ERα is mainly mediating the For actionsthis of estrogen and is consideredon as more for skeletal role o specific
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