Carol and Mike Werner/Science Source

Hormone secreted by bones may help us escape danger

Adrenaline. The word is synonymous with any activity that gets our blood racing, whether it be encountering a rattlesnake or watching the latest horror movie. But a new study reveals that when it comes with our body’s stress response, adrenaline may be less important than another hormone, one that seeps out of our bones.

Our skeleton is much more than a rigid scaffold for the body, says geneticist Gérard Karsenty of Columbia University. Our bones secrete a protein called osteocalcin, discovered in the 1970s, that rebuilds the skeleton. In 2007, Karsenty and colleagues discovered that this protein acts as a hormone to keep blood sugar levels in check and burn fat. Later, his group showed that the hormone is important for maintaining brain function and physical fitness, restoring memory in aged mice and boosting performance during exercise in old mice and people. The findings led Karsenty to hypothesize that animals evolved bony skeletons to escape danger.

The new study furthers that argument. Karsenty and colleagues exposed mice to several stressors, including a mild electric shock to the foot and a whiff of fox urine, a scent that triggers an innate fear response. Then, the researchers measured the osteocalcin in the animals’ blood.

Within 2 to 3 minutes of being exposed to a stressor, levels of osteocalcin in the mice quadrupled, the team reports today in Cell Metabolism. A classic stressor in people had a similar effect: When the researchers asked volunteers to speak in front of an audience, osteocalcin levels also spiked.

Next, Karsenty’s group set out to determine whether osteocalcin is required to trigger fight-or-flight mode, an involuntary physical reaction to threat. The mode includes a racing pulse, heavier breathing, and a spike in blood sugar; the response provides the body extra fuel for a speedy escape. When the team put mice genetically engineered not to make osteocalcin through the same stressors as the nonengineered mice, the rodents barely reacted. In normal mice, a single injection of osteocalcin was enough to trigger a full flight-or-fight reaction—even without a stressor.

By probing the neural connections between the rodents’ brains and their skeletons, the team discovered how osteocalcin unleashes fight-or-flight mode. When a brain region called the amygdala detects danger, it instructs bone cells called osteoblasts to release osteocalcin into the bloodstream, the researchers found. Osteocalcin, in turn, tamps down activity in the parasympathetic nervous system–nerve fibers that slow heart rate and breathing. This takes the brakes off the sympathetic nervous system, unleashing the body’s stress response, including the release of adrenaline, Karsenty says.

The findings suggest osteocalcin—not adrenaline—is the gatekeeper that determines when bodies shift into fight-or-flight mode, Karsenty says. They also help explain why rodents that have had their adrenal glands removed and people who don’t produce much adrenaline because of medical conditions can still experience intense physical reactions to danger.

The study is “definitely newsworthy” and supports the hypothesis that bones evolved to help animals escape predators and other threats, says Patricia Buckendahl, a bone physiologist at Rutgers University in New Brunswick, New Jersey, who was not involved with the work. Buckendahl presented the first evidence that osteocalcin acts as a stress hormone in rats 20 years ago, but no one took the idea very seriously at the time, she says. “I’ve always said bones are a heck of a lot more than a place to store calcium.”