Estrogen Signaling in Arcuate Kiss1 Neurons Suppresses a Sex-Dependent Circuit That Promotes Dense Strong Bones in Female Mice

Abstract

Classification Major: Biological Sciences Classification Minor: Medical Sciences or PhysiologyFemale Brain-Bone Connection Ablating ERa 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.

Should We Make More Bone or Not, As Told by Kisspeptin Neurons in the Arcuate Nucleus

“…Interestingly, in our hands using these same alleles, we failed to detect obvious changes in the female skeleton. 10 Although no obvious anatomical or functional sex differences within Kiss1 ARC neurons have been reported, our laboratory uncovered Kiss1 ARC neurons as critical regulators of sex-dependent nutrient partitioning and skeletal metabolism in female rodents using a combination of different genetic models as well as stereotaxic surgery. 10 Deleting ERα signaling in the ARC using the Esr1 floxed allele 36 and genetic or viral mediated Cre-deletion resulted in a massive increase in female bone mass without changes to food intake.…”

“…Thus, the very high bone mass in our three different mouse models likely stems from an expansion of pre-osteoblasts rather than an increase in sympathetic tone or decrease in bone resorption. 10 No changes in circulating pituitary hormones were observed, including follicle-stimulating hormone (FSH), a proposed modulator of skeletal homeostasis. 38,39 Nor did we detect changes in circulating gonadal steroids including estradiol or testosterone.…”

“…Interestingly, we and others show that Kiss1 transcripts or a knock-in GFP reporter are upregulated after deleting ERα. 10,25 This interplay appears to be highly relevant in Kiss1 ARC neurons prior to the onset of puberty when stimulation of truncal and axial bone growth is initiated. [40][41][42] Perhaps part of the initial prepubertal skeletal growth spurt in females just prior to puberty, and with the concomitant rise in gonadal hormones, can be partly attributed to enhanced kisspeptin signaling in the ARC.…”

“…[1][2][3][4][5][6][7][8] Recently, however, it has been suggested that central kisspeptin signaling plays a broader role by coordinating the onset of puberty with metabolic parameters, such as nutrient sensing. [9][10][11][12][13] Here, we will discuss an additional and unexpected emerging role of Kiss1 ARC neurons in controlling whole-body skeletal homeostasis, highlighting recent studies that link both central and peripheral kisspeptin signaling to bone density and outlining important questions to be answered in this developing field (►Fig. 1).…”