Bony Vertebrates Release Bone-Derived Hormone Osteocalcin in Response to Stress, Study Finds

A new study, published in the journal Cell Metabolism, shows that humans and other bony vertebrates need a hormone called osteocalcin to develop an acute stress response, a function critical to survival in the wild; when they encounter an immediate danger, a brain-derived signal stimulates the release of osteocalcin from bone. This fight-or-flight pathway is distinct from others mediated by hormones released by the adrenal glands, such as cortisol, adrenaline, and norepinephrine.

Berger et al found in mice 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. Image credit: Berger et al, doi: 10.1016/j.cmet.2019.08.012.

Berger et al found in mice 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. Image credit: Berger et al, doi: 10.1016/j.cmet.2019.08.012.

The acute stress response, also known as the fight-or-flight response, is mediated by the sympathetic nervous system and plays a critical role in helping animals react to potentially life-threatening situations.

The adrenal glands, which sit on top of the kidneys, release a variety of hormones such as adrenaline, norepinephrine, and cortisol. This triggers a cascade of wide-ranging physiological responses, including an increase in temperature, heart rate, respiration rate, blood pressure, and energy expenditure, preparing the muscles for action.

One conundrum about the acute stress response is that glucocorticoid hormones such as cortisol require hours to alter physiological responses, which seems inconsistent with the need for an immediate response to danger.

“Although this certainly does not rule out that glucocorticoid hormones may be implicated in some capacity in the acute stress response, it suggests the possibility that other hormones, possibly peptide ones, could be involved,” said Dr. Gérard Karsenty, from Columbia University Vagelos College of Physicians and Surgeons.

Dr. Karsenty and colleagues suspected that bone-derived hormones could contribute to the acute stress response, based on their hypothesis that the original purpose of bone was to respond to danger.

Bone protects internal organs from trauma, allows animals to move and escape danger, and mediates hearing, which is one way to detect threats.

Moreover, the bone-derived hormone osteocalcin is known to increase muscle function during exercise, which is necessary for animals attempting to escape danger, and to enhance memory, which is needed in the wild to remember the locations of food and predators.

In support of this idea, the researchers found that blood levels of the bioactive form of osteocalcin, but not other bone-derived hormones, rose by 50% in mice that were restrained for 45 minutes, and by 150% 15 minutes after they received a stressful stimulus.

Mice exposed to a cotton swab soaked with a component of fox urine also showed a rise in osteocalcin levels, which peaked at 2.5 minutes and remained steady for at least 3 hours. Similarly, circulating levels of bioactive osteocalcin rose in humans exposed to stress from public speaking and cross examination.

Genetic experiments in mice showed that osteocalcin was necessary for a robust increase in energy expenditure, circulating glucose, temperature, and heart rate upon exposure to stressors. Moreover, a single injection of osteocalcin was sufficient to trigger the acute stress response.

Consistent with past research on the fight-or-flight response, the stress-related surge in osteocalcin in mice depended on a brain region called the amygdala, also known as the brain’s fear center. It did not, however, require the adrenal glands.

“Osteocalcin could explain past observations of an intact flight-or-flight response in humans and other animals lacking glucocorticoids and additional molecules produced by the adrenal glands,” Dr. Karsenty said.

Additional experiments revealed the specific chain of events. Acute stressors trigger bone-forming cells called osteoblasts to take up the neurotransmitter glutamate, released by nearby neurons present in bone, through the Glast transporter.

Once inside osteoblasts, glutamate inhibits the activity of an enzyme that inactivates osteocalcin. After being released from osteoblasts, the activated hormone signals through the Gprc6a receptor to decrease the firing of upper airway and liver parasympathetic neurons involved in rest-and-digest activities.

This leaves the activity of the sympathetic nervous system unopposed, triggering fight-or-flight-related physiological responses.

“The present characterization of osteocalcin as a stress hormone provides a conceptual framework that can capture most osteocalcin-regulated physiological processes,” Dr. Karsenty said.

“Indeed, the ability of osteocalcin to facilitate the acute stress response, favor memory, and enhance muscle function during exercise suggests that osteocalcin confers a survival advantage to bony vertebrates that live in a hostile environment such as the wild.”

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Julian Meyer Berger et al. Mediation of the Acute Stress Response by the Skeleton. Cell Metabolism, published online September 12, 2019; doi: 10.1016/j.cmet.2019.08.012

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