While the role of bones has long been limited to that of an inert structure dedicated to protecting other organs, studies in recent years have revealed a much broader function, including the production of osteocalcin. This hormone is believed to be involved in several vital functions of the human body. However, its lifespan in the blood is short, which hinders its performance.
In a study recently published in the journal eLife, the team of Mathieu Ferron, Director of the Research Unit in Molecular Physiology and Associate Research Professor at the Montreal Clinical Research Institute (IRCM), unveiled an optimized version of the hormone that could be the basis for innovative therapies. Mathieu Ferron is also an Accredited Professor at the Université de Montréal and an Assistant Professor at McGill University.
Although its lifespan in human blood is about ninety minutes, osteocalcin is believed to play a central role in maintaining health throughout life. On the one hand, the hormone helps to regulate blood sugar by increasing the production of insulin and acting on the metabolism of glucose and fats. On the other hand, it acts on muscle mass, in addition to having beneficial effects on brain functions, improving memory and reducing depression.
Mathieu Ferron and his team know it well: the importance of osteocalcin is undeniable, and its understanding is essential for improving the living conditions of thousands of people struggling with serious health problems. That is why, for several years, the team has been tirelessly studying osteocalcin, in order to understand its many facets.
A Modified Osteocalcin to Preserve Health
Like many hormones, osteocalcin is vulnerable to enzymes that have the power to break it down quickly, making it unstable in the blood. Mathieu Ferron's team therefore sought ways to remedy this problem. It was through an alteration of the sequence of the human osteocalcin protein, by attaching a small group of sugars to it, that the team was able to produce a more resistant osteocalcin protein, optimizing its efficiency to hours.
The team came up with this idea after they found that the hormone was much more stable in another species, the mouse, due to a difference in the osteocalcin protein. Absent in humans, this difference, called O-glycosylation, consists of a small group of sugars that protect the hormone from degradation in mice.
Tested in vitro in a test tube, the team's modified version of osteocalcin showed significantly improved stability in the blood. It was also found to be more stable in vivo in mice. Concretely, it means that the modified hormone could potentially allow the use of osteocalcin as a treatment for people with diabetes, muscle weakness or cognitive decline.
A Promising Path Towards New Therapies
'We are particularly enthusiastic about these results, because by controlling the stability of osteocalcin, we are giving ourselves the means to respond to several health issues. This discovery is a first step towards further studies in humans,' said Omar Al Rifai, PhD student in Mathieu Ferron's lab and first author of the study.
For Mathieu Ferron, these results come in continuation of prior important discoveries on osteocalcin. As a matter of fact, in 2017, his team achieved a major breakthrough. They unveiled, in the renowned Journal of Clinical Investigation, hitherto unknown aspects of the functioning of osteocalcin, and more importantly the role of furin, an enzyme involved in several metabolic functions of the human body.
“Our study demonstrates the importance of studying the function and regulation of hormones in more than one animal species. Indeed, had we not been interested in osteocalcin in mice, we would have never known that glycosylation affects its stability, since the human hormone is not modified in this way,' explained Mathieu Ferron. 'This is, in my opinion, a great example of how essential basic research is, as no one can predict which fortuitous findings could lead to more concrete applications at the clinical level. '
About the Study
The research project was conducted at the IRCM Integrative and Molecular Physiology Research Unit by Omar Al Rifai, Catherine Julien, Julie Lacombe and Mathieu Ferron. Denis Faubert, from the IRCM Proteomics Discovery Platform, as well as Erandi Lira-Navarrete, Yoshiki Narimatsu and Henrik Clausen, from the University of Copenhagen also collaborated on the study.
The research received financial support from the Canada Research Chairs Program, the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, the IRCM Foundation and the Fonds de recherche du Québec – Santé.
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