The Quest to Discover the Bone Aging Mechanism

It is well known that bones become less dense and more brittle as we age, but the detailed mechanism is still relatively unclear. My research focuses on discovering how bones undergo senescence at the cellular level.

I am a basic researcher focusing on bone tissue, but I am also a dentist. My primary focus is on bone senescence, and I am also involved in bone regeneration research, which is a core theme of my lab. In addition, I provide dental care to patients several times a week.

When I first enrolled in dental school, I had no clear picture of what I wanted to do in the future—just a vague idea of something like being a local dentist. But at graduate school I soon got hooked on research—it was fascinating. In graduate school, I was engaged in periodontal disease research, but later, I had the opportunity to study abroad in the U.S. in a lab specializing in the craniofacial region. That’s where I was introduced to bone tissue research. After completing my research on the immune mechanisms of osteocytes in the U.S., I decided to embark on a new project—studying bone senescence.

I was inspired to apply for support under the Japan Agency for Medical Research and Development’s (AMED) Advanced Research & Development Programs for Medical Innovation out of a desire to contribute to the development of dental medicine. Between my lab research and my dental practice, I am happy to be engaged in rewarding work.

Shedding Light on the Relationship Between Kinetic Load and Bone Senescence

In general, our physical functions decline with age and we become less physically active. This reduces the mechanical stress placed on our bones. My hypothesis is that this decrease in mechanical stress may be closely connected with bone senescence and so, thanks to the support of AMED under its PRIME program, I am working to shed light on that mechanism in my research project, Elucidating the Mechanisms of Osteocyte Senescence and Its Pathophysiological Significance Through a Mechanobiology Approach. Mechanobiology is the study of the effects of forces on cells and tissue.

The cells that compose bone include osteocytes, which comprise more than 95% of the bone, as well as osteoblasts and osteoclasts, which are actually involved in bone metabolism. The osteocytes, which I am focusing on, are not only components of bone, but also serve as a “command post” that senses the mechanical load applied to bone and issues metabolic commands to osteoblasts and osteoclasts. My research tests the hypothesis that the loss of mechanical stress accelerates osteocyte senescence, resulting in metabolic dysregulation and bone loss, and seeks to shed light on the molecular mechanism by which osteocytes control metabolism by converting mechanical signals into biochemical signals. Once this mechanism is well understood, I believe that even if the mechanical stress on bone decreases with aging, we may be able to prevent or alleviate bone mineral loss by activating biochemical signals through the development of drugs and other means.

In this study, we conduct experiments using cultured cells and mice. The cell experiments use equipment that can reproduce a microgravity environment similar to that of outer space, and compare osteocytes cultured in an environment without the mechanical stress of gravity with osteocytes cultured in a normal environment to examine the levels of genes and proteins expressed.

A device that can reproduce the low-gravity environment of the International Space Station, around one 1000th of the gravity experienced on the Earth’s surface.

The results of the experiments showed that osteocytes cultured in a microgravity environment showed accelerated cellular senescence, as expected. Moreover, when the levels of various proteins produced in osteocytes were examined, genes and proteins were found to be reduced in osteocytes with accelerated cellular senescence compared to osteocytes cultured normally.

These genes and proteins may play an important role in mechanical signaling, and if my hypothesis is correct, osteocytes deficient in these proteins would not function in signaling under mechanical stress, resulting in rapid senescence. To test this hypothesis, I am using genetic modification technology to create osteocytes and mice deficient in the gene that produces the key protein, and am conducting further experiments.

Beyond that, we hope to investigate the actual functions of these genes and proteins in detail to elucidate the mechanism of osteocyte senescence.

Broadening the Scope of Dental Care to Incorporate Medical and Pharmacological Approaches

This AMED-supported study focuses on the long bones of the leg, which are subject to considerable mechanical stress. If I can elucidate the mechanism of osteocyte senescence in these long bones during the PRIME research period, I would like to build on this to advance research on aging in the jaw bone. The jawbone is subjected to the mechanical stress of daily mastication and is therefore thought to be uniquely affected by the senescence and disease process.

Currently, surgical procedures (cutting and filling) are the mainstay of dental treatment, and internal medical treatment is rarely used. Given this situation, I believe that there is still much potential for basic biological research in the field of dentistry, including bone research. My ultimate goal is to elucidate the senescence mechanism of the jawbone that supports the teeth, and to create unprecedented dental treatments, including internal medical and pharmacological approaches.