Scientists just discovered a hormone that may solve a long-standing biological mystery.
It's difficult to prove you've identified a new hormone — a chemical signal that directs behavior in distant cells, often by traveling through the bloodstream. To be sure, you need to confirm where it's made, which tissues it affects and that it can be found in the bloodstream, senior study author Holly Ingraham, a professor and vice-chair of cellular and molecular pharmacology at the University of California, San Francisco, told Live Science.
"Most have been discovered, so it's pretty novel to actually uncover a new hormone," said Dr. Sundeep Khosla, a physician-scientist at Mayo Clinic in Rochester, Minnesota, who was not involved in the research. "They make a pretty convincing case that this is really a hormone."
Scientists had previously found the substance in mammals, including humans, Khosla noted, but they didn't know it was a hormone. The new study shows that the chemical — which the researchers have dubbed "maternal brain hormone" — travels from the brain to bone-forming cells, where it helps build bone, according to the new study, published Wednesday (July 10) in the journal Nature.
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This bone-building comes into play after pregnancy, when estrogen levels plummet and the demand for calcium skyrockets as the body starts making milk. Normally, estrogen strengthens bones and prevents their calcium from being stripped away. Thus, it's been unclear how bones retain much of their strength during breastfeeding and then recover soon after weaning.
The new hormone "adds an important piece to that whole biology that we didn't know before," Khosla told Live Science. What's more, although it's important in the postpartum period, the new hormone can also boost bone growth in males, the researchers showed.
"This is an equal-opportunity hormone — it works in both males and female bones and skeletal stem cells," Ingraham said. "If we can develop it into a therapy, [it] will work in both males and females." The hormone could theoretically help speed up fracture repair, treat osteoporosis and prevent premature bone loss triggered by medical treatments.
Hunting for a hormone
The new study builds upon research in mice published in 2019, in which Ingraham and colleagues found a way to boost bone density and strength by up to 800%. This dramatic effect was mediated by cells in the brain's hypothalamus, a hormone-making structure. Blocking estrogen in specific cells in the hypothalamus supercharged bone growth. However, this trick only worked in female mice, not in males, suggesting this particular pathway only exists in females.
The researchers theorized that, when estrogen is switched off, these cells in the female brain somehow prompt the body to channel energy into growing bone. The question was, how do these cells get the word out? So in the new study, they looked for a blood-borne molecule that would relay the message.
This quest was like hunting for a needle in a haystack, because hormones present in the blood exist in only "miniscule amounts," Ingraham told Live Science.
The team first confirmed that their culprit was in the blood using mice with blocked estrogen signaling, and thus, extra-thick bones. Normal mice infused with blood from these modified mice showed dramatic bone growth. The team also transplanted bone-growing stem cells and whole bones into different parts of the modified mice; these transplants too showed enhanced growth, suggesting the hormone was both potent and in widespread circulation.
Related: What is bone density?
The team then looked at gene activity in the hypothalamus and found that, in the big-boned mice, a specific gene in these cells was very active: CCN3, which encodes instructions for a protein. (This is the protein that the researchers propose should now be called "maternal brain hormone.")
Not much is known about the CCN3 protein, but historically, people didn't think it was a hormone. It was thought to do its job locally, rather than entering circulation, Ingraham said. Nonetheless, the group's experiments pointed to this protein as the hormone they sought.
It's particularly novel because hormones made in the hypothalamus normally talk to the pituitary gland — a master hormone-maker attached to the base of the brain. The pituitary gland would then pass messages from the hypothalamus on to the body, but in this case, the hypothalamus-made hormone "talks directly to bone," Khosla said.
The team even showed that, in elderly mice, the bone-boosting hormone can accelerate the healing of fractures.
"When I saw that fracture repair data, I knew that this absolutely had to be real," Ingraham said. "It's just so phenomenal that you can take these 2-year-old male mice … and see that sort of repair."
Finally, the scientists revealed that, in the postpartum period, CCN3 naturally goes up in female mice's brains. If you block that increase, the mice's bones rapidly grow weaker as they continue to lactate. This uptick in CCN3 still needs to be confirmed in humans, Khosla said, but the mouse data suggest that the hormone is key to keeping bones strong during breastfeeding. For now, though, it's unclear how that switch actually gets flipped in the brain.
"What is it about this [postpartum] period that turns this thing on in the brain, in those neurons?" Ingraham said. "We don't know." That mystery will take much more work to solve — and it may just reveal additional hormones in the process, she said.
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