‘To feel it in one’s bones.’ The expression goes all the way back to Shakespeare’s time, meaning to know something intuitively if not quite with certainty. Back in the early nineties when geneticist Dr. Gerard Karsenty of Columbia University Medical Center was just getting his own lab started, everybody “knew” that the skeletal system and the endocrine system were discrete, that the former’s primary function was to support our flesh and flab and that the latter’s main job was to produce hormones to serve as our molecular messengers. No one suspected back then what Dr. Karsenty intuitively understood in his bones and then conclusively demonstrated in his peer-reviewed research: the skeletal system is part of the endocrine system. The reason? Only the skeletal system produces a hormone -- osteocalcin -- proven to be critical in controlling for mood, memory, and strength, even for male fertility and the flight-or-fight response.
“When I started my own lab,” Dr. Karsenty admits in a recent interview with podcaster Paul Skallas, “I thought most major discoveries had already been made. I had some anxiety as to what I would be able to contribute to science.”
As it turned out, Dr. Karsenty could contribute a paradigm shift in the true Kuhnian sense of the concept, one that has revolutionized our understanding of mammalian physiology and biology. Not too bad.
“We now recognize that the body is far more networked and interconnected than most people think,” says Dr. Karsenty. “No organ is an island. The skeleton often seems to play a surprising role. If insulin impacts bone, bone should help regulate insulin. If testosterone has an influence on bone mass, the skeleton should act on the testes. And, most fundamentally, just as the brain talks to the skeleton, bone should help regulate the brain. It is not what I learned in medical school. We continue the search to learn how this bidirectional influence works.”
Let’s start with the bare bones of it. Osteocalcin is secreted by osteoblasts, our bone-forming cells. However, osteocalcin does not remain in our bones as once thought, but instead functions as a molecular messenger carried by the bloodstream to regulate functions such as glucose metabolism, male fertility, exercise, memory, and acute stress response. In short, bones are active agents of the mammalian endocrine system, producing osteocalcin not present in other organs and vital to our homeostasis.
Back in the early nineties when the technology to genetically modify mice first became available, Dr. Karsenty engineered a few to lack the gene for osteocalcin, expecting he would find problems with their bones. Instead, their bones were basically fine, but their little rodent tummies were full of fat. For some reason, these mice were not metabolizing glucose efficiently and were, in human terms, pre-diabetic. Not only that, but they were also unusually docile, exhibiting no annoying flight-or-fight behavior such as biting researchers’ fingers. Further, while male mice producing high levels of osteocalcin had abundant testosterone and bred frequently, the male mice that did not produce osteocalcin had abnormally low levels of testosterone and were sterile. (For any dudes wishing to remember this particular finding, here’s a free mnemonic: ‘positive boners’ equal mice with osteocalcin; ‘negative boners’ equal mice without. You’re welcome.)
From such intriguing beginnings, Dr. Kersenty and his team have since pieced together an entirely new picture of this critical hormone. “Osteocalcin is a little bit like the Godfather,” Dr. Kersenty says. “It controls hitmen. It’s upstream of insulin. It’s upstream of testosterone. It’s upstream of neurotransmitters of the parasympathetic nervous system. It’s the regulator of regulators.” Research has now even shown that osteocalcin crosses the blood-brain barrier, binding to neurons of the brainstem, midbrain, and hippocampus, preventing anxiety and depression and enhancing learning and memory.
But why does the body make osteocalcin in bone? Why not just pump it out from some gland in the endocrine system? Dr. Kersenty has a hypothesis. “Bone was invented to escape danger,” he says. “Not only does the skull protect the brain and the ear’s three bones allow us to hear, but the osteocalcin from the bones allows you to mobilize glucose as a source of energy. Put yourself 100,000 years ago,” he continues, “living in an unfriendly environment. Memory was here to tell you where the predator was an hour ago, where the food was yesterday. And even if you had a huge memory, if you could not run, you could not survive.” Research has shown in mice, rats, and humans facing danger, circulating osteocalcin levels rise within minutes. “Osteocalcin—not adrenaline,” says Dr. Karsenty, “is the gatekeeper that determines when bodies shift into fight-or-flight mode.”
Good to know because, while we’re no longer fighting saber-tooth cats and cave bears, life definitely still has its struggles. Problem is, osteocalcin decreases with age, typically peaking in women in their twenties and in males in their thirties. Could negative aspects associated with aging -- decreased bone mass, inefficient glucose metabolism, memory loss and increased risk for depression -- be related to lower levels of osteocalcin? Dr. Kersenty strongly suspects the answer is yes. Fortunately, there is a way to counteract these risks: exercise. Since bone, like muscle, is living tissue, it responds to exercise by becoming stronger. The best bone-building exercises are weight-bearing exercises, ones in which you take on gravity by doing stuff like running and dancing. Resistance exercises, weight-lifting for example, also build bones. In either case, it’s sweat well spent. “In my view,” says Dr. Kersenty, “a higher bone mass means a greater capacity for osteocalcin production.” And increased levels of this hormone will help you live better: better exercise, better metabolism, better male fertility, better memory, better mood. So… better get going!
Written by William Harwood