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

Candice B. Herber, William C. Krause, Liping Wang, James R. Bayrer, Alfred Li, Matthew Schmitz, Aaron Fields, Breanna Ford, Zhi Zhang, Michelle S. Reid, Daniel K. Nomura, Robert A. Nissenson, Stephanie M. Correa () and Holly A. Ingraham ()
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Candice B. Herber: University of California San Francisco
William C. Krause: University of California San Francisco
Liping Wang: University of California San Francisco
James R. Bayrer: University of California San Francisco
Alfred Li: University of California San Francisco
Matthew Schmitz: School of Medicine University of California San Francisco
Aaron Fields: School of Medicine Mission Bay Campus University of California San Francisco
Breanna Ford: University of California
Zhi Zhang: University of California Los Angeles
Michelle S. Reid: University of California Los Angeles
Daniel K. Nomura: University of California
Robert A. Nissenson: University of California San Francisco
Stephanie M. Correa: University of California San Francisco
Holly A. Ingraham: University of California San Francisco

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-08046-4

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