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Nat Commun. 2019 Jan 11;10(1):163. doi: 10.1038/s41467-018-08046-4.

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

Author information

1
Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, 94158, USA.
2
VA Medical Center Endocrine Unit and Bone Imaging Core Facility, University of California San Francisco, San Francisco, CA, 94158, USA.
3
Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94158, USA.
4
Graduate Program in Developmental Biology, School of Medicine University of California San Francisco, San Francisco, CA, 94158, USA.
5
Department of Orthopedic Surgery, School of Medicine Mission Bay Campus University of California San Francisco, San Francisco, CA, 94158, USA.
6
Department of Nutritional Sciences and Toxicology, University of California, Berkeley Berkeley, CA, 94720, USA.
7
Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, 90095, USA.
8
Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, 94158, USA. stephaniecorrea@ucla.edu.
9
Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, 90095, USA. stephaniecorrea@ucla.edu.
10
Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, 94158, USA. holly.ingraham@ucsf.edu.

Abstract

Central estrogen signaling coordinates energy expenditure, reproduction, and in concert with peripheral estrogen impacts skeletal homeostasis in females. Here, we ablate estrogen receptor alpha (ERα) in the medial basal hypothalamus and find a robust bone phenotype only in female mice that results in exceptionally strong trabecular and cortical bones, whose density surpasses other reported mouse models. Stereotaxic guided deletion of ERα in the arcuate nucleus increases bone mass in intact and ovariectomized females, confirming the central role of estrogen signaling in this sex-dependent bone phenotype. Loss of ERα in kisspeptin (Kiss1)-expressing cells is sufficient to recapitulate the bone phenotype, 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 diverting calcium and energy stores from bone building when energetic demands are high. Our work reveals a previously unknown target for treatment of age-related bone disease.

PMID:
30635563
PMCID:
PMC6329772
DOI:
10.1038/s41467-018-08046-4
[Indexed for MEDLINE]
Free PMC Article

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