mouse being chased by a lynx
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When faced with situations of real or perceived sudden danger the body sets in motion a series of physiological changes in preparation either for a fight or to take flight. This acute stress response (ASR) includes the rapid heart rate and rapid breathing that we may all be familiar with, and the release of glucose to fuel muscles in preparation for action. It’s widely thought that the ASR is triggered by hormones, including adrenaline, that are released by the adrenal glands. However, new research in mice and in humans by a Columbia University Irving Medical Center-led team suggests that the ability to mount an ASR actually depends on the hormone osteocalcin, which is produced in our bones.

The findings support the concept that the skeleton evolved in part as “a tool to fight acute danger,” commented senior investigator Gérard Karsenty, MD, PhD, chair of the department of genetics and development at Columbia University Vagelos College of Physicians and Surgeons. “In bony vertebrates, the acute stress response is not possible without osteocalcin … the notion that bone mediates the stress response is totally novel, as is the notion that the adrenal glands do not mediate the stress response … It completely changes how we think about how acute stress responses occur.”

Karsenty and colleagues report on their studies in Cell Metabolism, in a paper titled, “Mediation of the Acute Stress Response by the Skeleton.”

The ASR—the fight-or-flight response—is ultimately under the control of the sympathetic nervous system, and it plays a crucial role in helping animals to react to life-threatening situations. As part of the response, the adrenal glands release hormones including adrenaline, norepinephrine, and cortisol, which triggers the cascade of physiological responses, including an increase in temperature, heart rate, respiration rate, blood pressure, and energy expenditure. It’s all designed to prepare the muscles for action. The fight-or-flight pathway is distinct from others mediated by hormones released by the adrenal glands.

However, the pieces of the puzzle don’t all quite fit. Glucocorticoid hormones such as cortisol don’t trigger immediate, fast-response physiological responses. “As steroids, glucocorticoid hormones act mainly, albeit not only, at the transcriptional level and need hours to regulate physiological processes, something that seems inconsistent with the need for an immediate response,” the authors wrote. This suggests that the adrenal hormones may not be acting alone in triggering the ASR. The need for hormones other than adrenaline to orchestrate the fight-or-flight response is also suggested by the fact that rodents without adrenal glands, and human patients with adrenal insufficiency, can still mount a normal ASR. And in rodents, “Genetic experiments indicate that this is due to the doubling of circulating osteocalcin,” the authors stated.

“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,” noted Karsenty, who suspected that bone-derived hormones could contribute to the acute stress response, based on the hypothesis that the original purpose of bone was to respond to danger. “This is why, in considering that the original purpose of bone was to escape danger, we asked whether bone-derived hormones contribute to the ASR in bony vertebrates,” the authors continued.

In fact, bone does carry out protective functions. “The view of bones as merely an assembly of calcified tubes is deeply entrenched in our biomedical culture,” Karsenty said. His lab had previously demonstrated that osteocalcin released by the skeleton travels through the bloodstream to the pancreas, the brain, muscles, and other organs. Subsequent studies had also shown that osteocalcin helps to regulate metabolism by increasing glucose uptake, improves memory, and impacts on animals’ speed and endurance.

“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 added. If bone evolved as a means to escape danger, then it’s not unreasonable that it may also be involved in the acute stress response, which is activated in the presence of danger.

In support of the idea that osteocalcin may be critical to mounting an ASR, the newly published results of experiments carried out by Karsenty and his team showed that blood levels of the bioactive form of osteocalcin, but not other bone-derived hormones, increased in mice placed under stressful conditions. Ostocalcin levels rose by 50% in animals that were restrained for 45 minutes, and increased by 150% 15 minutes after mice received a stressful stimulus. Exposing mice to the scent of a predator—using a cotton swab soaked with a component of fox urine—also led to a rise in blood osteocalcin levels, which peaked at 2.5 minutes and remained steady for at least 3 hours.

Interestingly, studies have also shown that circulating levels of bioactive osteocalcin are increased in humans exposed to stress from public speaking or cross-examination. “Similar observations have been made in adrenal-insufficient dogs that were stressed, and in humans, heart rate, blood pressure, and energy expenditure increase to the same extent in glucocorticoid-deficient patients and control individuals who are exposed to a stressor-like high-intensity exercise,” the team stated.

Genetic experiments in mice, in addition, showed that osteocalcin was necessary for the stress-triggered increases in energy expenditure, circulating glucose, temperature, and heart rate. It was possible to trigger an ASR in test animals by giving them a single osteocalcin injection.

Consistent with previous research on the fight-or-flight response, the team showed that stress-related surges in osteocalcin in mice required the activity of the amygdala region of the brain, which is known as the brain’s fear center. However, the adrenal glands weren’t requisite to an ASR. “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,” Karsenty said.

Further experiments unpicked the chain of events in an ASR. They showed that acute stressors trigger bone-forming osteoblasts to take up the neurotransmitter glutamate, which is released by nearby neurons present in bone, through the Glast transporter. “It has long been known that osteoblasts have the necessary machinery to take up glutamate, yet the functions of glutamate in osteoblasts had remained elusive,” the team stated. Once inside osteoblasts, glutamate inhibits the activity of an enzyme that inactivates osteocalcin. “Our work reveals that one such function is to allow the release of bioactive osteocalcin.”

The activated osteocalcin is then released from the osteoblasts, and 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,” Karsenty stated. “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 … Clinically, it suggests that we respond to stress better when we are young and have high osteocalcin than when we are older and have much less of it,” Karsenty commented.

The authors acknowledge that their findings don’t exclude the possibility that other organs may contribute to the development of an ASR. Nevertheless, they wrote, “… these findings support the hypothesis that a purpose of the endocrine functions of bone is to allow animals living in the wild to escape danger … The present characterization of osteocalcin as a stress hormone provides a conceptual framework that can capture most osteocalcin-regulated physiological processes. Indeed, the ability of osteocalcin to facilitate the ASR, 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.”

The authors say the findings also raise the question of why cortisol rises during the acute stress response. They plan to continue their research both to answer this question and to expand their studies to primates and to help uncover the neuronal road map from the brain to the bone. “I have no doubt that there are many more new inter-organ signals to be discovered,” Karsenty concluded, “and these interactions may be as important as the ones discovered in the early part of the 20th century.”

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