A maternal brain hormone that builds bone

Muriel E. Babey, William C. Krause, Kun Chen, Candice B. Herber, Zsofia Torok, Joni Nikkanen, Ruben Rodriguez, Xiao Zhang, Fernanda Castro-Navarro, Yuting Wang, Erika E. Wheeler, Saul Villeda, J. Kent Leach, Nancy E. Lane, Erica L. Scheller, Charles K. F. Chan, Thomas H. Ambrosi () and Holly A. Ingraham ()
Additional contact information
Muriel E. Babey: University of California, San Francisco
William C. Krause: University of California, San Francisco
Kun Chen: University of California, Davis
Candice B. Herber: University of California, San Francisco
Zsofia Torok: University of California, San Francisco
Joni Nikkanen: University of California, San Francisco
Ruben Rodriguez: University of California, San Francisco
Xiao Zhang: Washington University
Fernanda Castro-Navarro: University of California, San Francisco
Yuting Wang: Stanford University School of Medicine
Erika E. Wheeler: University of California, Davis
Saul Villeda: University of California, San Francisco
J. Kent Leach: University of California, Davis
Nancy E. Lane: University of California, Davis
Erica L. Scheller: Washington University
Charles K. F. Chan: Stanford University School of Medicine
Thomas H. Ambrosi: University of California, Davis
Holly A. Ingraham: University of California, San Francisco

Nature, 2024, vol. 632, issue 8024, 357-365

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41586-024-07634-3

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