Hormone produced during breastfeeding speeds bone fracture repair in mice

Babies need plenty of calcium to grow and it usually comes from the milk of a breastfeeding caregiver. But during breastfeeding, that calcium is coming from the caregiver’s own bone reserves and needs to be replaced. Research published Wednesday in Nature has identified a hormone in mice responsible for telling the body to build bone density during breastfeeding. On top of that, the researchers were able to show that this hormone can help build bone density in mice that aren’t actively breastfeeding, potentially paving the way for a new therapeutic that could quicken bone fracture repair or reverse osteoporosis (2024, DOI: 10.1038/s41586-024-07634-3).

Holly Ingraham, a physiologist at the University of California, San Francisco, who led the research, has spent the last 15-plus years trying to improve the understanding of female physiology. She hopes this will help the millions of people with chronic diseases that are more common in women than men. In 2019, her lab had fortuitously discovered a female mouse mutant with unusually high bone mass, and despite a lack of experience working on bone physiology, Ingraham pivoted her lab’s focus toward discovering the root of this phenotype.

First, Ingraham and her group used a classical technique called parabiosis to determine if whatever was responsible for the high-bone-mass phenotype was moving through the bloodstream. Using this technique, the researchers took two mice and sewed their legs together so that they would share a circulatory system and blood supply. When a wild-type mouse was joined with a high-bone-mass mutant, bone density in the wild-type mouse increased, suggesting that some factor that helped build bone mass was circulating in the blood.

Then, to identify candidate genes, the team used single-cell RNA sequencing, among other experiments, and determined that a transcription factor produced in the brain during breastfeeding called Cellular Communication Network Factor 3, or CCN3, was the hormone most likely mediating the buildup of extra bone mass. When Ingraham and colleagues gave purified CCN3 to mice with bone fractures, the fracture repair process sped up. And they found that it could even rebuild bone density in older mice.

The fracture repair data are what got Ingraham excited about the potential for this research to translate to a therapeutic, even though for now this work is limited to a proof of concept in mice.

Patricia Ducy, a pathologist at Columbia University, calls the research “a beautiful study. It’s a gain-of-function experiment that’s very comprehensive and really a lot of fun.” But Ducy adds that “a lot of work has to be done to use this molecule as a therapeutic tool.”

Ingraham knows this and is already thinking about the next step. “Identifying the receptor is key for really taking this to the next step in terms of a potential therapeutic,” she says.