Ever consider what basic scientists are discovering about the inner workings of bone? Wonder what might be lurking in the cells of your diabetic or obese patients? How many times have you thought, “The skeletal system doesn’t get as much attention as the heart or lungs in medical education?” With the evolving research on the role of bone, we may just find that the role of the skeletal system will grow in importance.
Dr. Gerard Karsenty, Professor and Chair of Genetics and Development at Columbia University Medical Center, is utilizing both an evolutionary and clinical approach to bone modeling and remodeling. And he has found interesting connections with energy metabolism. Dr. Karsenty: “This work started nearly 15 years ago from the observation that bone is an organ necessary for the survival of vertebrates. If there is no bone modeling then we can’t grow or walk; thus, bone modeling is the engine of bone biology. Bone is the only tissue in the body that contains a cell type, the osteoclast, whose only function is to destroy the host tissue. It’s as if bone was going through an autoimmune disease process on a daily basis. The fact that bone destroys and rebuilds itself daily—and that it is the organ that covers the most surface area of our bodies—means that a great deal of energy is being directed toward bone.”
Insulin Glucose Metabolism/User Meiquer/Wikimedia Commons
Observations from the clinical realm bear out these connections, says Dr. Karsenty. “Children with anorexia nervosa do not grow; adults with this condition are osteoporotic. Then there is the fact that obesity often protects people from osteoporosis. These indicate a direct link between the amount of food intake and the amount of bone we make. Given this, we hypothesized that there is a common regulation of bone mass and energy metabolism. Fundamentally, this hypothesis was motivated by the co-existence of bone with its ‘partner’ hormones during evolution. One such hormone is leptin, which appears during evolution with the osteoclast (leptin doesn’t appear evolutionarily with cartilage, but with the ability to model and remodel bone). Leptin regulates in the same direction as bone mass and appetite.”
“Our research revealed that there is a partial gain of functioning in leptin signaling. We realized that these mice have a normal appetite and breed normally but they are osteoporotic, meaning that the threshold of leptin signaling to affect bone mass is lower than to affect appetite and reproduction. This is consistent with the fact that leptin emerges during evolution with bone. Our team went on to identify the functioning of leptin in the brain, and how it relates bone cells. At present we are attempting to more fully understand the signal transduction pathway in leptin target neurons in the brain.”
Is Bone an Endocrine Organ?
The researchers then took a systems-wide leap. “We then asked if energy metabolism regulates bone mass, i.e., ‘is bone an endocrine organ?’ The team identified a hormone made by osteoblasts—osteocalcin—and found that it is a function of osteocalcin to promote glucose homeostasis. This is important because if you have an excess of this hormone you are protected from diabetes and obesity. The idea that bone is in fact an endocrine organ that regulates energy metabolism was unknown before our work.”
Their work was conducted with the assistance of some (relatively) cooperative mice…knockout mice that they found to be diabetic. “Insulin itself regulates energy metabolism by acting through bone. We have known for years that insulin favors glucose metabolism by favoring glucose uptake in the target tissue (typically the muscle, fat and liver). If you inactivate insulin signaling in muscle and fat, you don’t affect glucose metabolism in mice that are fed a normal diet. But when you inactivate the insulin receptor in osteoblasts, the bone forming cells, mice become glucose intolerant. This says that bone is an important tissue for whole body glucose homeostasis.”
“Our lab, as well as others, are now trying to determine the mechanism of action of osteocalcin in target cells. Our other goals are to identify the osteocalcin receptor and the extracellular regulators of its activity. It is very much a work in progress. The bottom line is that this work could put bone on the same educational footing as liver and other insulin target organs. Over time, it may change the face of orthopedic education itself.”
Unbeknownst to Dr. Karsenty, Dr. Thomas Clemens, Director the Center for Musculoskeletal Research at Johns Hopkins University, was simultaneously studying the same problem but from a slightly different angle. He notes, “In an attempt to learn more about diabetic patients’ susceptibility to bone fragility, we knocked out the insulin receptor in osteoblasts…and serendipitously created the same knockout mice as Dr. Karsenty’s team.”
Dr. Clemens, Editor-in-Chief of the Journal of Bone and Mineral Research, adds, “These knockout mice began to get fat, and displayed signs of insulin resistance along with low osteocalcin levels. The situation worsened with time, with the mice continuing to gain weight and developing very high blood sugar, extreme glucose intolerance, and insulin resistance. This biochemical picture exactly mirrored the finding from Dr. Karsenty’s group and pointed toward osteocalcin as the causative hormonal agent. What clinched the story for us was that infusion of osteocalcin into the knockout mice improved their metabolic problems”
The Bone-Pancreas Axis of Energy
Still, Dr. Clemens warns that much more work is needed. “We are getting a first glimpse of what all of this means and how the bone-pancreas axis functions in controlling energy expenditure. And we are beginning to see evidence in the literature suggesting that this may be the case in humans as well. The next steps will be to establish a bone-pancreas connection in people by studying the effects of administration of osteocalcin on their blood sugar and energy expenditure.”
“Our findings raise all sorts of new questions whose answers may have profound implications in diagnosis and management of patients with metabolic disturbances. Do osteoporosis drugs that influence bone resorption alter blood sugar? If so, how might this affect patients with diabetes who receive antiresorptive therapy? Alternatively, could it be possible eventually to design a single drug that can concurrently target osteoporosis and type 2 diabetes? Time will tell.”
So it seems that bone is far from a stagnant, structural affair. It’s much busier than it looks…and more important than we ever thought.
