By Birthing and caring for a newborn can be hard on a mother’s bones. Estrogen, which helps regulate bone growth, drops precipitously after birth, and lactation saps the skeleton of calcium. Yet nursing moms somehow maintain strong, dense bones. A hormone released from the brain may be the reason why, a study in mice suggests.
When estrogen levels drop after birth, the hormone CCN3 may take the role of boosting bone stem cell activity, leading to increased tissue production, researchers report July 10 in Nature. This molecule originates in the hypothalamus, a brain structure that helps regulate appetite and body temperature. Besides possibly solving the mystery of nursing mothers’ strong bones, the finding could also point to a way to better heal fractures and fight bone loss in old age.
The study “identifies a new direct loop between the hypothalamus and bone, which is, I think, totally unexpected,” says Sundeep Khosla, a bone researcher at the Mayo Clinic in Rochester, Minn., who was not involved in the study.
In the new research, scientists set out to determine why blocking an estrogen receptor in the hypothalamus resulted in female mice with particularly high bone density. Compared with normal mice, the mutant mice “had a super significantly increased number of bone stem cells,” says stem cell biologist Thomas Ambrosi of the University of California, Davis.
Since the hypothalamus also plays a key role in appetite, the researchers examined diet to see how that would affect bone density and the hormones being produced. A key piece of the puzzle fell into place when the team found that mutant mice placed on a high-fat diet reverted to having a normal bone density. An analysis of which bone-strengthening factors decreased in those mice let the team narrow the list of potential candidates from hundreds to just a handful, says Muriel Babey, an endocrinologist at University of California, San Francisco.
Scientists then added the substances to mouse stem cells in a petri dish — and discovered that when treated with CCN3, bits of bone formed. The team also found that CCN3 levels spiked in female rats during lactation, suggesting that CCN3 plays a role in supporting maternal bone strength during breastfeeding, when estrogen levels drop.
Next, Ambrosi’s team tested CCN3 in elderly mice with bone fractures, which typically do not heal well. Applying a hydrogel patch containing the hormone to injury sites stimulated bone formation, allowing for faster recovery. If the hormone works on human skeletal stem cells in a similar way, that could lead to new treatments for osteoporosis (SN: 9/20/18).
Though there are numerous drugs to prevent bone loss, Khosla says, “we’re still limited in terms of the drugs that stimulate bone formation, and particularly do it in a sustained way — not just for months, but over years.” Due to CCN3’s tissue-building properties, future drugs based on this hormone could potentially increase bone regeneration.
The study “highlights how much important biology and physiology is happening during reproductive life stages,” says coauthor William Krause, a pharmacologist also at UC San Francisco. “There’s potentially a lot of biology there that remains to be covered.”
