It would be ironic today to keep using the term skeletal in its literal context while referring to our bones. One important breakthrough in medical research in the past few years has been the reclassification of bone as an endocrine organ. With this, our traditional understanding of the bone’s identity has undergone a drastic reboot.
It has been revealed that the skeletal system is not merely a framework of bones, cartilage and ligaments that supports, shapes and makes us mobile. It has been pointed out that the bones are literally chatterboxes involved in constant crosstalk with other organs and directly influencing multiple life processes (including glucose metabolism).
Say hello to a bone secreted hormone – osteocalcin
The key player here is osteocalcin, mainly its undercarboxylated form, a bone hormone secreted during bone-cell remodelling that has been shown to interact with pancreas and favour insulin secretion and better glucose absorption.
This triggered a cloudburst of activity in the field of bone endocrinology since the last decade involving top researchers including Dr Gerard Karsenty, professor and chair of the Department of Genetics and Development, Columbia University Medical Centre, New York City. Their main objective: to unravel the dynamics of this insulin-bone pathway in our cells so that it could be enhanced through targeted therapeutic intervention to tame the global epidemic of type 2 diabetes.
“Osteocalcin has several functions related to glucose homeostasis. It favours insulin secretion by pancreatic beta cells; second is that it favours glucose uptake at least in muscle and possibly in other tissues,” Prof Dr Karsenty told Happiest Health in an online interaction. Homeostasis is a state of equilibrium or balance between multiple components involved in physiological processes in our body.
Prof Dr Karsenty said osteocalcin also favours gluconeogenesis in the liver, which sort of counterbalances any possibility of hypoglycaemia (low blood glucose levels) in the body due to additional insulin secreted through this loop. During gluconeogenesis the liver processes and release additional glucose, mainly from non-carbohydrate sources.
Prof Dr Karsenty is credited as the first researcher to have discovered osteocalcin’s role in glucose metabolism back in 2007.
However, it took a couple of years more for his research team to finally announce in 2010 that the new insulin pathway of undercarboxylated osteocalcin, pancreatic beta cells, insulin and also adipose tissues could play a pivotal role in balancing our blood glucose levels and body weight management.
In a media release at that time, Columbia University had said that stimulation of the bone-insulin pathway could lead to a better cure or management strategy for type 2 diabetes in the future.
“This feed forward loop is only between osteoblasts that makes osteocalcin and pancreatic cells that make insulin,” Prof Dr Karsenty told Happiest Health. “Osteocalcin favours insulin secretion and insulin favours secretion of bioactive osteocalcin (undercarboxylated).”
Welcome to the bone matrix
Bones are perhaps the most dynamic organs of the body — appearing inert but yet caught in a constant chaotic state of modelling and remodelling to ensure that they could keep pace and adapt to various physiological changes and trauma as people age on in life.
This is basically ensured by the death of old bone cells to get re-absorbed into the blood (resorption) and simultaneous formation of new bone cells to replace these old cells. Our bones are generally made up of a calcium-rich intercellular bone matrix and three types of cells (osteoblasts, osteoclasts and osteocytes).
- osteoblasts, which are responsible for bone formation
- osteoclasts are the ones for bone resorption
- osteocytes, which are mainly a variant of osteoblasts involved in sensory functions pertaining to bone formation and remodelling
“Osteocalcin is a protein hormone predominantly released by osteoblasts (responsible for bone synthesisation and mineralisation) and physiologically plays an important role in bone formation and remodelling,” Prof Dr Antonio Brunetti, professor of endocrinology, University of Magna Graecia of Catanzaro and director of Operative Unit of Endocrinology, AOU Mater Domini, Catanzaro, Italy, told Happiest Health in an online interaction. “Recent studies have shown that osteocalcin is also involved in other important processes not directly linked with bone physiology, such as regulation of whole-body glucose metabolism.”
Osteocalcin is in fact one of the most abundant bone protein hormones in the intercellular bone matrix. Osteocalcin was always considered as a marker and agent of osteoblastic bone formation, but it was only after researchers started to look closer at this hormone that it became evident that bone formation could actually be just one of the many functions of this dynamic hormone. It was soon found that osteocalcin is actually an undercover endocrinal agent embedded in the bone matrix involved in an array of physiological function including glucose metabolism and even energy expenditure, ageing and cognitive abilities.
“The endocrine function of osteocalcin appears to be primarily related to its under-carboxylated form, and to a lesser extent to its carboxylated form, but the available scientific evidence in this context is conflicting,” said Prof Dr Brunetti. “Regardless of the osteocalcin carboxylation state, investigations from our own group and others have shown that elevated blood glucose concentrations (hyperglycaemia) in patients with diabetes are consistently associated with low circulating levels of osteocalcin. Indeed, there is a suggestion that this bone-derived hormone, either directly or indirectly, stimulates the production and release of insulin by pancreatic beta cells. In normal conditions, insulin helps to ensure that blood glucose is taken up by the liver, adipose tissue and skeletal muscle after a meal, preventing high blood glucose peaks.”
Loop before you leap
Prof Dr Mathieu Ferron, director of the Molecular Physiology Research Unit at the Montreal Clinical Research Unit (ICRM) and associate research professor and Canada Research Chair in Bone and Energy Metabolism at the ICRM, told Happiest Health in an online interaction that there was an insulin receptor located on osteoblasts and some of the initial research work on osteocalcin and glucose metabolism involved removal of these insulin receptors from specially bred lab mice. Prof Dr Ferron was also part of the team that Prof Dr Karsenty led in 2010 when they officially pointed out the link between bones, glucose uptake and insulin secretion.
“Our data (Ferron 2010, Cell) suggest that osteocalcin stimulate insulin production, and that in return insulin acts on bone to promote osteocalcin release,” Prof Dr Ferron said. “We observed that the insulin receptor is present on osteoblasts. Removing insulin receptor specifically in this cell type resulted in surprising effects in mice: they had more fat, less insulin and higher blood glucose. We also found that serum osteocalcin was reduced in these animals. In other words, insulin through its action on bone regulates whole body glucose level! Through a series of studies we next established that insulin stimulates not only osteoblast to produce more osteocalcin, but also osteoclasts, the bone-resorbing cells, which is responsible of decarboxylating and activating osteocalcin.”
Interestingly, it has been pointed out that Prof Dr Karsenty and his team was trying to unravel the role of osteocalcin in bone formation and decided to experiment after removing the gene responsible for osteocalcin when they realised that it did not have a serious impact on the bone formation, but the mice soon became obese, glucose intolerance and also started showing symptoms of cognitive impairment.
Further research by their team revealed that bone resorption was integral to the completion of this feed forward loop as regular carboxylated osteocalcin changes into under carboxylated form as a direct result of high acidic conditions caused due to bone resorption by osteoclasts and sets up this feed forward loop in motion.
“In addition to these correlative studies a few articles have reported that human osteocalcin can impact human beta cell function in a petri dish (in vitro) or in a diabetic mouse transplanted with human beta cells (in vivo),” Prof Dr Ferron said.
Prof Dr Ferron said there are about 100 cross-sectional studies in humans which show that higher level of osteocalcin in the blood are associated with lower glucose or that lower osteocalcin is associated with higher risk of diabetes.
“In support of this view, recent in vitro experiments from our lab have highlighted that exposure to conditioned medium from human MG-63 osteoblasts*, which are low in osteocalcin content because of an impaired insulin receptor signalling, can actually reduce the insulin-producing response of cultured pancreatic β-cells to glucose stimuli,” Prof Dr Brunetti said. (*MG 63 osteoblasts area-specific human osteoblast like cells used for lab experiments).
In a joint response to Happiest Health, Prof Dr Brunetti along with his colleagues Dr Maria Mirabelli and Dr Alessandro Salatino from the University of Magna Graecia said, “In fact, according to current research, obese individuals who are insulin resistant have a different pattern of secreted adipokines than people who are not obese. The past few decades have also witnessed an extensive disentangling of the insulin receptor signalling pathway, with the identification of non-canonical insulin target tissues that appear to play an important role in whole-body glucose homeostasis, including the bone.”
They also pointed out that the adipose-bone and pancreas axis of osteocalcin will be deeply impaired in obese people and those with diabetes as they would be already affected by insulin resistance leading to high blood sugar levels.
Better diabetes management options?
One of the main obstacles that researchers had to face while trying to enhance the effect of osteocalcin in humans was to ensure that it could stay longer in our blood stream without being broken down by enzymes. It was found that osteocalcin in mice was always five to 10 times higher than in humans.
In 2020 a group of researchers including Prof Dr Ferron published their research stating that osteocalcin in mice was more stable than that in humans because it has a group of sugars attached to its protein structure, which is not present in human osteocalcin. Researchers are now working on modified human osteocalcin that could be maintained at high levels in our blood without getting filtered out by the kidney or broken down by enzymes.
The potential of the ongoing research into osteocalcin’s blood sugar regulatory role could be gauged to an extent from the fact that Prof Dr Ferron’s work on osteocalcin, ‘A hormone produced by bone to treat Diabetes’, was adjudged as one among the 15 diabetes-related research projects from across the world to be bestowed with the End Diabetes: 100 Awards in 2021. Constituted by the Canadian Diabetes Association, the award carries an annual grant of $100,000 for three years. Last year was also the centennial anniversary of the discovery of insulin by Dr Frederick Banting, Dr Charles H Best and JJR Macleod in Toronto.
“My lab is currently working on a modified human osteocalcin protein that is more stable in the blood, with the goal of using it as a new therapeutic approach for diabetes,” Prof Dr Ferron said. “Osteocalcin is a protein produced in bone tissue that travels to our pancreas, fat and muscles to regulate blood glucose. Harnessing the specialized function of this protein could become a ground-breaking treatment for type 2 diabetes.”
Happiest Health also posed the question about osteocalcin’s role in diabetes management in the near future to Prof Dr Karsenty. He confirmed that his team was also working on a project to ensure better management of blood sugar using this bone hormone.
Dr Tom Babu, medical director, consultant diabetologist and endocrinologist, Silverline Hospital, Kochi, Kerala told Happiest Health that it was fascinating that the bone is being now considered as an endocrine organ. He said it holds promise for therapeutic interventions in the future and more research is being carried out in this direction.
“I would definitely keep watching this space,” Dr Babu said. “In my clinical practice I have seen that people with better bone health seem to be better placed with regards to metabolic diseases.”
