2. Academic Validation
  3. A maternal brain hormone that builds bone

A maternal brain hormone that builds bone

  • Nature. 2024 Aug;632(8024):357-365. doi: 10.1038/s41586-024-07634-3.
Muriel E Babey # 1,  William C Krause # 2,  Kun Chen 3,  Candice B Herber 2 4,  Zsofia Torok 2,  Joni Nikkanen 2 5,  Ruben Rodriguez 2 6,  Xiao Zhang 7,  Fernanda Castro-Navarro 2,  Yuting Wang 8,  Erika E Wheeler 3 9,  Saul Villeda 10,  J Kent Leach 3 9,  Nancy E Lane 11,  Erica L Scheller 7,  Charles K F Chan 8,  Thomas H Ambrosi 12,  Holly A Ingraham 13
Affiliations

Affiliations

  • 1 Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Francisco, San Francisco, CA, USA.
  • 2 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
  • 3 Department of Orthopaedic Surgery, University of California, Davis, Sacramento, CA, USA.
  • 4 Denali Therapeutics, South San Francisco, CA, USA.
  • 5 Department of Integrative Biology, University of California, Berkeley, Berkeley, CA, USA.
  • 6 Carmot Therapeutics, Berkeley, CA, USA.
  • 7 Department of Medicine, Washington University, St Louis, MO, USA.
  • 8 Institute for Stem Cell Biology and Regenerative Medicine and Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
  • 9 Department of Biomedical Engineering, University of California, Davis, Davis, CA, USA.
  • 10 Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.
  • 11 Department of Medicine, Division of Rheumatology, University of California, Davis, Sacramento, CA, USA.
  • 12 Department of Orthopaedic Surgery, University of California, Davis, Sacramento, CA, USA. thambrosi@ucdavis.edu.
  • 13 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. holly.ingraham@ucsf.edu.
  • # Contributed equally.
PMID: 38987585 DOI: 10.1038/s41586-024-07634-3
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.

Figures