15 April 2019:
Ablation of estrogen receptor alpha (ERα) in the medial basal hypothalamus results in a robust bone phenotype only in female mice that ends in exceptionally strong trabecular and cortical bones, the density of which surpasses that reported in other mouse models.
The role of estrogens in regulating reproduction in females is known, but the role it plays in the brain remains uncharacterized. Estrogen works jointly with vitamin D and calcium to preserve the regulation of bone turnover. After menopause, as the levels of estrogen in the body decline, the rate at which bones are rebuilt increases and the skeleton begins to lose more mineral content than it produces. Central estrogen signaling coordinates energy expenditure, reproduction, and, in concert with peripheral estrogen, affects skeletal homeostasis in females. In this study, Herber and collegues ablated estrogen receptor alpha (ERα) in the medial basal hypothalamus and this action caused the mice to gain weight and become less active. To the authors’ surprise, the weight gain was due to an 800 percent increase in bone mass. Aside from an increased density, the bones of the animals also had an increase in strength. This increased strength and density did not falter as the mice aged, leading to a robust bone phenotype only in female mice that resulted in exceptionally strong trabecular and cortical bones, the density of which surpassed that of other mouse models . Stereotaxic-guided deletion of ERα in the arcuate nucleus increases bone mass in intact and ovariectomized females, underlining 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 strong neuroskeletal circuit. The precise neuronal or humoral signals that promote the high mass bone phenotype in females remain to be determined. However, this phenotype is independent of changes in leptin or estradiol and is not directly influenced by ERα neurons in the ventro-medial hypothalamus (VMH). These findings differ from prior reports linking leptin deficiency to high trabecular bone mass  via a circuit involving suppression of serotonergic signaling in the VMH  or direct effects of leptin on bone . In conclusion, this study demonstrated that estrogen plays a different role in the blood than it does in the brain. In the blood, estrogen contributes to bone stability, while in the brain, estrogen seems to limit bone formation. 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. This study reveals a new target for treatment of osteoporosis.
Professor of Obstetrics and Gynecology, University of Barcelona, Spain
- 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.Estrogen signaling in arcuate Kiss1 neurons suppresses a sex-dependent female circuit promoting dense strong bones Nature Communications 2019; 10(1): 163.
- Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 2000; 100: 197–207.
- Yadav VK, Oury F, Suda N, Liu ZW, Gao XB, Confavreux C, Klemenhagen KC, Tanaka KF, Gingrich JA, Guo XE, Tecott LH, Mann JJ, Hen R, Horvath TL, Karsenty G. A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell 2009; 138: 976–989.
- Turner RT, Kalra SP, Wong CP, Philbrick KA, Lindenmaier LB, Boghossian S, Iwaniec UT. Peripheral leptin regulates bone formation. J Bone Miner Res 2013; 28: 22–34.