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Brain Hormone Protects Maternal Bones During Lactation

    Written by: Alla Katsnelson, Ph.D | Issue # 122 | 2024

    • The study identified CCN3 as a hormone that promotes bone growth during lactation in mice. 
    • CCN3 levels were elevated in lactating mice and dropped after weaning.. The hormone also drove bone growth when delivered to the blood of both male and female mice, regardless of their age. 
    • It’s still unknown whether CCN3 is transmitted to babies through breastmilk and affects their bone growth. It’s also unknown whether CCN3 is elevated in lactating women, though it is known to drive bone growth in human bone stem cells. 
    • The discovery of CCN3 may point to therapies that treat osteoporosis, fracture repair, dental implants and cartilage regeneration

    A newly discovered brain hormone called CCN3 ramps up in postpartum lactating mothers to promote bone formation and keep bones strong, reports a new study in mice (1). The findings may explain how mammals prevent bone breakdown after giving birth as their bodies siphon calcium from their bones and use it to produce milk for their infants, says Holly Ingraham, a cellular and molecular pharmacologist at the University of California, San Francisco, who led the work. According to Ingraham, the discovery of CCN3 may also point to new ways of treating osteoporosis, bone fractures, or other conditions. 

    Estrogen is a well-known bone builder. That’s why in menopause, when estrogen levels drop, women become especially prone to osteoporosis and fractures. But estrogen drops sharply at another time in a woman’s life, too—the postpartum period. After surging during the end of pregnancy, estradiol, the main form of estrogen in women of reproductive age, falls during lactation. Female rodents (2), macaque monkeys (3) and humans (4) experience a high level of bone loss and bone turnover as calcium from maternal bones is redirected toward milk production. 

    “It really made sense that mother nature would come up with a way to regenerate bone during this period, so that the body can strip away bone and not have the mother disintegrate into jelly,” Ingraham says. 

    Ingraham’s team stumbled onto CCN3’s bone-building role when they found that deleting estrogen receptors from specific neurons in the arcuate nucleus, a region of the hypothalamus, counterintuitively caused female mice to grow extra strong and massive bones (5). “We had to figure out how this extraordinary bone phenotype came about,” she says. 

    The researchers suspected that this bone-building effect was switched on by a molecule circulating in the blood. They homed in on a molecule they had identified earlier by looking at changes in gene expression in the neurons engineered to lack estrogen receptors. That molecule turned out to be CCN3, which stands for cellular communication network factor 3. Further experiments revealed that when mice began lactating, CCN3 levels rose. “There was a 100% correlation with when the phenotype came on,” Ingraham said. When they weaned their young, CCN3 dipped back down.

    When Ingraham and her colleagues blocked the hormone before mice got pregnant, their bones degenerated during pregnancy, and their offspring grew poorly.  Additionally, when the hormone was boosted in the blood of mice that were not lactating, “then you start building up bone strength in both males and females, young and old,” she says. 

    Some researchers have argued that there must be an off switch to this mechanism, but Ingraham argues that the body may not need one. She and her colleagues instead posit that a signal that travels to the brain to put CCN3 into high gear. Then, after lactation, estrogen levels resume, bringing the body’s usual bone-building mechanism back online. CCN3 gets dialed down but still remains at low levels during the transition. “The brain integrates all these signals to decide what to do—especially in female physiology,” she says. 

    The researchers have not yet looked at CCN3’s activity in lactating women, but it is known that adding CCN3 to skeletal stem cells in a dish causes them to make something like cartilage and bone,” Ingraham says. “So we know that the human cellular target is responsive to this factor.” What’s still in question is whether lactating women have elevated CCN3 levels. Because the hormone works at very low levels, she adds, “the current reagents aren’t sensitive enough, so quite frankly we really need better technology” to detect it in blood. It’s also still unknown whether CCN3 gets into breastmilk to affect the bones of the infants consuming it, says Ingraham. “I think that’s a fascinating question.”

    Ingraham is currently fielding calls from companies who are interested in harnessing CCN3 therapeutically. “They see the potential here for osteoporosis, fracture repair, dental implants and cartilage regeneration,” she says. “I think it would be wonderful if this could be a drug.” So far, the paper has been downloaded around 25,000 times, she says, “and I’m going to guess a fair fraction of that is women” concerned about bone loss. She adds: “We are living longer, and we understand that our bones and our skeleton are absolutely critical for healthy aging.”

    References

    1. Babey ME, Krause WC, Chen K, Herber CB, Torok Z, Nikkanen J, Rodriguez R, Zhang X, Castro-Navarro F, Wang Y, Wheeler EE, Villeda S, Leach JK, Lane NE, Scheller EL, Chan CKF, Ambrosi TH, Ingraham HA. A maternal brain hormone that builds bone. Nature. 2024;632(8024):357-365.
    2. VanHouten JN, Wysolmerski JJ. Low estrogen and high parathyroid hormone-related peptide levels contribute to accelerated bone resorption and bone loss in lactating mice. Endocrinology. 2003;144(12):5521-9.
    3. Lees CJ, Jerome CP. Effects of pregnancy and lactation on bone in cynomolgus macaques: histomorphometric analysis of iliac biopsies. Bone. 1998;22(5):545-9.
    4. Augustine M, Boudreau R, Cauley JA, Majchel D, Nagaraj N, Roe LS, Sood P, Stewart AF, Horwitz MJ. Bone Mineral Density During and After Lactation: A Comparison of African American and Caucasian Women. Calcif Tissue Int. 2023;113(4):426-436.
    5. 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. Nat Commun. 2019;10(1):163.