A maternal brain hormone that builds bone

• 成果类型: Article
• 署名作者: Babey, Muriel E.; Krause, William C.; Chen, Kun; Herber, Candice B.; Torok, Zsofia; Nikkanen, Joni; Rodriguez, Ruben; Zhang, Xiao; Castro-Navarro, Fernanda; Wang, Yuting; Wheeler, Erika E.; Villeda, Saul; Leach, J. Kent; Lane, Nancy E.; Scheller, Erica L.; Chan, Charles K. F.; Ambrosi, Thomas H.; Ingraham, Holly A.
• 署名单位: University of California System; University of California San Francisco; University of California System; University of California San Francisco; California State University System; California State University Sacramento; Washington University (WUSTL); Stanford University; Stanford University; University of California System; University of California Davis; University of California System; University of California San Francisco; University of California System; University of California Davis; University of California System; University of California Berkeley
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3811
• DOI: 10.1038/s41586-024-07634-3
• 发表日期: 2024-08-08
• 关键词: estrogen-receptor-alpha; rna-seq; lactation; postpartum; pregnancy; peptide; neurons; identification; hypothalamus; regeneration

摘要

In lactating mothers, the high calcium (Ca2+) demand for milk production triggers significant bone loss1. Although oestrogen normally counteracts excessive bone resorption by promoting bone formation, this sex steroid drops precipitously during this postpartum period. Here we report that brain-derived cellular communication network factor 3 (CCN3) secreted from KISS1 neurons of the arcuate nucleus (ARCKISS1) fills this void and functions as a potent osteoanabolic factor to build bone in lactating females. We began by showing that our previously reported female-specific, dense bone phenotype2 originates from a humoral factor that promotes bone mass and acts on skeletal stem cells to increase their frequency and osteochondrogenic potential. This circulatory factor was then identified as CCN3, a brain-derived hormone from ARCKISS1 neurons that is able to stimulate mouse and human skeletal stem cell activity, increase bone remodelling and accelerate fracture repair in young and old mice of both sexes. The role of CCN3 in normal female physiology was revealed after detecting a burst of CCN3 expression in ARCKISS1 neurons coincident with lactation. After reducing CCN3 in ARCKISS1 neurons, lactating mothers lost bone and failed to sustain their progeny when challenged with a low-calcium diet. Our findings establish CCN3 as a potentially new therapeutic osteoanabolic hormone for both sexes and define a new maternal brain hormone for ensuring species survival in mammals. A brain-derived hormone, CCN3, is newly identified to have a role as an osteoanabolic factor to build bone in lactating females and in the viability of offspring.