ISSN 1662-4009 (Online)

ESPE Yearbook of Paediatric Endocrinology (2019) 16 1.4 | DOI: 10.1530/ey.16.1.4

Estrogen signaling in arcuate Kiss1 neurons suppresses a sex-dependent female circuit promoting dense strong bones

Herber CB, Krause WC, Wang L, Bayrer JR, Li A, Schmitz M, Fields A, Ford B, Zhang Z, Reid MS, Nomura DK, Nissenson RA, Correa SM & Ingraham HA

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA;

To read the full abstract: Nat Commun 2019;10:163.

Central estrogen signaling via estrogen receptor alpha (ERα) coordinates energy expenditure, reproduction and, in concert with peripheral estrogen, impacts skeletal homeostasis. Here, the authors showed that eliminating ERα in kisspeptin arcuate nucleus neurons resulted in high bone mass phenotype in female mice only.

To show these interesting results, the authors first studied bone mass in mice with a deletion of ERα in medio-basal hypothalamus (MBH) neurons (Esr1Nkx2-1Cre mice). They observed a change in energy balance only in females. In addition, they observed an elevated bone density only in females Esr1Nkx2-1Cre which persisted five weeks after ovariectomy. Hormonal homeostasis was not disturbed in these mice.

To define which MBH neurons are involved in the central control of bone mass, the authors eliminated ERα in the ventro-medial hypothalamus or the arcuate nucleus (ARC), and observed the increase of bone mass only in the second model. Furthermore, they show that the central control of bone mass by ERα is mediated through ARC kisspeptin neurons.

Altogether, this work establishes a brain-bone axis in female, but not in male, mice. The mechanism of this central control is probably humoral, by molecules that remain to be discovered. The second question asked by the authors is how the ERα brain-bone pathway counteracts the positive peripheral effects of estrogen on bone remodeling. It would therefore be interesting to analyze whether this brain-bone axis is active in juvenile mice.