Characterized by a rise in heart rate, respiration, temperature, and adrenaline, the acute stress response, more commonly known as the fight-or-flight response, is a physiological reaction to dangerous or fearful situations. While a mammal’s sense of fear originates in the brain, a key mediator of the stress response derives, somewhat unexpectedly, from bone, according to a study published in Cell Metabolism today (September 12). Osteocalcin, a hormone secreted by bone cells, induces the fight-or-flight response by essentially deactivating the brakes that normally keep it in check, the research reveals.
The finding is “interesting and exciting” and “a big surprise,” says Clifford Rosen, a bone expert at the Maine Medical Center Research Institute who was not involved in the study. It raises the questions, he continues, “Why would the skeleton be an acute phase responder? Why would you bother to work through the skeleton?”
While skeletal biologist Gerard Karsenty of Columbia University does not have the answers, he certainly has a theory. Karsenty has been studying osteocalcin for more than two decades. As well as being one of the most abundant proteins in the body, he says, osteocalcin is important for a variety of physiological functions including memory retention, capacity for exercise, testosterone production, and insulin secretion. In these seemingly disparate functions, Karsenty sees a link. Maybe, during the evolution of vertebrates, he suggests, osteocalcin has become “a tool for animals to escape danger.” Exercise capacity, heightened memory, glucose handling, and even testosterone production, which helps build muscle, could all be explained by such a theory, he argues.
With this in mind, the next logical step, he says, “was to test if [osteocalcin] is implicated in the quintessential function needed to escape danger, which is the acute stress response.”
To induce the response, Karsenty’s team exposed mice, rats, and humans to known stressors. For the rodents these included electric shocks to the feet, physical restraint, and the odor of a predator’s urine, while the human subjects were submitted to a session of public speaking and cross-examination. In all cases, the stressors invoked a significant rise in the circulating levels of osteocalcin, but not of other bone hormones.
It certainly emphasizes . . . that this factor, osteocalcin, has a huge role that we hadn’t really even thought about.—Bruce McEwen, the Rockefeller University
Because the basolateral amygdala of the brain is thought to recognize, interpret, and process such stressors, Karsenty and colleagues investigated whether this brain region controlled osteocalcin release. Sure enough, when they inhibited neuronal activity in the basolateral amygdala of mice, osteocalcin levels no longer spiked in response to a stressor.
The team went on to show that mice lacking osteocalcin had a diminished stress response and that injection of the hormone in the animals was enough to evoke fight-or-flight physiological markers. They also showed that osteocalcin acts on the body’s parasympathetic nervous system. A subdivision of the autonomic nervous system and counterpart to the sympathetic system—thought to activate the fight-or-flight response—the parasympathetic system is believed to promote the equally essential but opposing physiological status known as rest-and-digest. The team found that neurons of the parasympathetic system expressed the osteocalcin receptor, and that while intravenous osteocalcin injection in wildtype mice provoked no electrophysiological change in sympathetic neuronal activity it significantly decreased the firing frequency of parasympathetic neurons.
“The idea that there is a factor from the bone that does this by attenuating parasympathetic activity is very novel, no question about it,” says neuroendocrinologist Bruce McEwen of the Rockefeller University who did not participate in the research. “It certainly emphasizes . . . that this factor, osteocalcin, has a huge role that we hadn’t really even thought about.”
The work “opens a whole new track of thinking and research,” McEwen continues. A track that could lead to investigations of how natural variations in people’s osteocalcin levels relate to stress, for example, as well as to “developing pharmacological agents” for stress regulation, he suggests. Ultimately, “whenever you have a new factor it gives opportunities for new kinds of interventions,” he says.
J. M. Berger et al., “Mediation of the acute stress response by the skeleton,” Cell Metabolism, doi:10.1016/j.cmet.2019.08.012, 2019.
Ruth Williams is a freelance journalist based in Connecticut. Email her at email@example.com or find her on Twitter @rooph.