The “fight or flight” response, is commonly believed to be triggered in part by the hormone adrenaline. But a new study from researchers at Columbia University suggests that bony vertebrates are not able to produce this response to danger without the skeleton.
The researchers found in mice and humans that almost immediately after the brain recognizes danger, it instructs the skeleton to flood the bloodstream with the bone-derived hormone osteocalcin, which is needed to turn on the fight or flight response.
“In bony vertebrates, the acute stress response is not possible without osteocalcin. It completely changes how we think about how acute stress responses occur,“
says senior investigator Gerard Karsenty, MD, PhD, chair of the Department of Genetics and Development at Columbia University Vagelos College of Physicians and Surgeons.
Fight Or Flight
When faced with a predator or sudden danger, the heart rate goes up, breathing becomes more rapid, and fuel in the form of glucose is pumped throughout the body to prepare an animal to fight or flee.
“The view of bones as merely an assembly of calcified tubes is deeply entrenched in our biomedical culture,“
Karsenty says. But about a decade ago, his lab hypothesized and demonstrated that the skeleton has hidden influences on other organs.
The research revealed that the skeleton releases osteocalcin, which travels through the bloodstream to affect the functions of the biology of the pancreas, the brain, muscles, and other organs.
A series of studies since then have shown that osteocalcin helps regulate metabolism by increasing the ability of cells to take in glucose, improves memory, and helps animals run faster with greater endurance.
Why does bone have all these seemingly unrelated effects on other organs?
“If you think of bone as something that evolved to protect the organism from danger - the skull protects the brain from trauma, the skeleton allows vertebrates to escape predators, and even the bones in the ear alert us to approaching danger - the hormonal functions of osteocalcin begin to make sense,“
Karsenty says. If bone evolved as a means to escape danger, Karsenty hypothesized that the skeleton should also be involved in the acute stress response, which is activated in the presence of danger.
If osteocalcin helps bring about the acute stress response, it must work fast, in the first few minutes after danger is detected.
In the new study, the researchers presented mice with predator urine and other stressors and looked for changes in the bloodstream. Within 2 to 3 minutes, they saw osteocalcin levels spike.
Similarly in people, the researchers found that osteocalcin also surges in people when they are subjected to the stress of public speaking or cross-examination. When osteocalcin levels increased, heart rate, body temperature, and blood glucose levels in the mice also rose as the fight or flight response kicked in.
In contrast, mice that had been genetically engineered so that they were unable to make osteocalcin or its receptor were totally indifferent to the stressor.
“Without osteocalcin, they didn’t react strongly to the perceived danger,” Karsenty says. “In the wild, they’d have a short day.“
As a final test, the researchers were able to bring on an acute stress response in unstressed mice simply by injecting large amounts of osteocalcin.
No Adrenaline Required
The findings may also explain why animals without adrenal glands and adrenal-insufficient patients - with no means of producing adrenaline or other adrenal hormones - can develop an acute stress response.
Among mice, this capability disappeared when the mice were unable to produce large amounts of osteocalcin.
“This shows us that circulating levels of osteocalcin are enough to drive the acute stress response,“
Physiology may sound like old-fashioned biology, but new genetic techniques developed in the last 15 years have established it as a new frontier in science.
The ability to inactivate single genes in specific cells inside an animal, and at specific times, has led to the identification of many new inter-organ relationships. The skeleton is just one example; the heart and muscles are also exerting influence over other organs.
The work was supported by the National Institutes of Health; a Ramalingaswamy Fellowship; a CIHR Fellowship, the Veterans Administration; and the Fraternal Order of Eagles Diabetes Research Center at the University of Iowa.
 Gerard Karsenty, et al. Mediation of the acute stress response by the skeleton. Cell Metabolism; http://dx.doi.org/10.1016/j.cmet.2019.08.012
 Cyrille B Confavreux, Robert L Levine, Gerard Karsenty. A paradigm of integrative physiology, the crosstalk between bone and energy metabolisms. Mol Cell Endocrinol. 2009 Oct 30; 310(0): 21–29.