Abstract
Hypothalamic neurons in the medial basal hypothalamus (MBH) have been shown to regulate modest changes in bone density in both males and females. Central estrogen signaling has also been implicated in altering bone mass in intact, but not estrogen-depleted female mice. While estrogen-responsive hypothalamic modules have been defined for coordinating energy expenditure and reproduction in females, the precise neurons involved in an estrogen-dependent putative brain-to-bone pathway remain poorly defined. Here, we ablate estrogen receptor alpha (ERα) in the entire MBH and find a massively dense bone phenotype only in female mice. Loss of ERα in the female MBH increases markers of bone morphogenic protein (BMP) signaling and osteoblast differentiation, resulting in exceptionally strong trabecular and cortical bones, whose density surpasses other reported mouse models. Acute ablation of ERα in the ARC by stereotaxic guided deletion increases bone mass in both intact and estrogen-depleted females, confirming the central role of estrogen signaling on skeletal homeostasis. Finally, we find that ablating ERα activity in kisspeptin (Kiss1) neurons is sufficient to recapitulate the effects on bone, identifying Kiss1 neurons as a critical node in this powerful neuroskeletal circuit. We propose that this newly identified female brain-to-bone pathway exists as a homeostatic regulator to divert calcium and energy stores from bone building when energetic demands are high. Our work reveals a previously unknown target for the treatment of age-related bone disease.
Significance Statement Our study defines central regulation of bone metabolism, alongside reproduction and energy balance, as a fundamental determinant of female physiology. Estrogen signaling in the brain is beneficial for energy expenditure and reproduction in female mice. Using three independent and intersectional strategies, we discovered that estrogen signaling in hypothalamic kisspeptin neurons is also a powerful negative regulator of bone metabolism. Ablating ERα in kisspeptin neurons results in a massive female-specific increase in bone density leading to exceptionally strong bones. When this neuroskeletal homeostatic circuit is broken in older and “post-menopausal” female mice, bone health improves. Our work provides a platform for further mechanistic investigations that might eventually provide new opportunities to counteract age-related osteoporosis in both women and men.
