Anyone who’s ever said they felt scared to their bones might have been speaking more literally than we knew. A new study out Thursday seems to show that in both mice and humans, bones secrete a hormone in reaction to stressful situations. What’s more, this bone hormone appears to be crucial to our fight-or-flight response, in a way completely separate from other well-known stress chemicals like adrenaline.


Gerard Karsenty, a geneticist at Columbia University, and his colleagues have long been interested in studying how our skeleton keeps us alive and healthy—not just by supporting us physically, but through the interactions it has with the rest of the body. Their work has centered on osteocalcin, a hormone produced by some of the same cells that make up bone. His and others’ earlier research has suggested that osteocalcin helps regulate diverse functions such as metabolism, muscle function during exercise, and fertility.

“What we found is that you do not necessarily need an ounce of the adrenal glands to produce this acute stress response, at least in mice.”


In this sense, osteocalcin works like a lot like other hormones produced by the glands and organs that make up our endocrine system. Because of this, Karsenty and his team have argued that the skeleton should be considered an endocrine organ. That line of thinking led Karsenty’s team to theorize that our skeletons could have evolved to help us better respond to stress, too, since that’s another pivotal function of the endocrine system. And if that’s the case, then osteocalcin should play a leading role there as well.

To test this theory, they first experimented with mice. They exposed the poor rodents to various sources of acute stress, such as by restraining them or having them sniff the urine of foxes, a common predator. Judging by their blood tests, the team found that stressed-out mice produced more osteocalcin within minutes of their ordeal.

They then moved on to people. But since fox urine doesn’t have quite the same effect on us, Karsenty instead asked volunteers to do some public speaking and then take questions. As expected, people’s blood pressure and heart rate went up, as did their levels of osteocalcin.

The team’s findings were published Thursday in Cell Metabolism.


Other genetic experiments in mice suggested that osteocalcin directly affects a part of the brain called the amygdala, a region well known for helping us process emotions like fear. But importantly, this pathway from our bones to our brains doesn’t seem to involve the adrenal glands—the organ located on top of our kidneys, long seen as the key to the fight-or-flight response.

It might even turn out that osteocalcin is more important to lighting a fire under us in the face of danger than our adrenal glands are. In mice bred to be unable to respond to osteocalcin, their fight-or-flight response was drastically muted, but the same wasn’t true when mice lacked their adrenal glands. These mice were still capable of feeling quickly stressed out.


“What we found is that you do not necessarily need an ounce of the adrenal glands to produce this acute stress response, at least in mice,” Karsenty said. “And this may explain why even people without adrenaline can still have an intact response.”

In Karsenty’s theory, adrenaline and other hormones aren’t worthless to our fight-or-flight response. For one, some of our nerve cells produce adrenaline and a related hormone called norepinephrine, too. His team thinks that the production of osteocalcin triggers the release of these hormones in the brain, which then regulate other aspects of our acute stress response. Our adrenal glands are probably still playing their own role, even if they’re not the starting gun that sends us going when we spot a tiger in the grass or a spider on the wall.


There’s still a lot of work to be done before we can rewrite the book on stress and adrenaline, though. That’ll involve further experiments with other test animals as well as people. But if nothing else, this is the latest bit of research to show that the body is even more complicated and interconnected than we have assumed it to be.

“We have not been studying the body as long as people think. We have been studying groups of cells, isolated from one another,” Karsenty said. “But what mouse genetics now allow is for us to look at the function of organs, and how hormones and molecules mediate their function, in an entire complex organism.”