NIH R01 Grant Concerning Bone Regeneration in Periodontitis
Dr. Toshihisa Kawai (DDS, PhD), Professor and Chair of the Department of Oral Science and Translational Research, College of Dental Medicine, was awarded with an NIH R01 grant ($2.0 M, including Diversity Administrative Supplements, 2020-2025) for the research project titled “Osteoimmunology of Retarded Bone Regeneration in Periodontitis.” This is his 4th NIH R01 grant awarded during his research career.
Periodontitis is one of the most prevalent diseases known to destroy tooth-supporting bone.
In the U.S., 40% of adults have some form of periodontitis, and 70% of adults 65 years and older have periodontitis. Periodontal diseases are mainly the results of infections and inflammation of the gums and bone that surround and support the teeth (according to CDC). Dr. Kawai’s group, for the first time, discovered that overactivation of bacteria-reactive lymphocytes in gum tissue causes pathogenic bone destruction in periodontitis and launched the paradigm of Osteoimmunology in periodontitis (Am J Pathol, 2006), which led to his first NIH grant funding (2002-2006). The above-noted R01 grant was awarded to the Kawai laboratory for identifying the molecules, OC-STAMP and Semaphorin 4D, responsible for destroying tooth-supporting bone and interrupting bone regeneration in periodontitis.
A strong body of evidence supports the idea that periodontitis is a risk factor for a variety of systemic diseases, such as Alzheimer’s disease (odds ratio 1.7), Rheumatoid arthritis (odds ratio 2.0), COPD (odds ratio 2.0), birth anomalies (odds ratio 6.3) and myocardial infarction (odds ratio 1.5). This can be attributed to the pathogenic property of periodontitis that permits periodontal bacteria to penetrate into the circulation and deliver bacterial virulence factors to remote organs. For example, a recent study found periodontal bacteria in the brain of patients with Alzheimer (2019). Therefore, for those who suffer with periodontitis, a large number of bacteria are pumped into blood circulation every day, just from eating or brushing teeth, quietly shortening longevity.
For the prevention and treatment of bone-destructive diseases, including osteoporosis and cancer bone metastasis, anti-resorptive drugs, such as bisphosphonates or Denosumab, are commonly used. However, patients who have been administered with large doses of these drugs develop a side effect known as “medication-related osteonecrosis of jaw (MRONJ)” after dental surgery, including tooth extractions and periodontal root planing. Although the molecular mechanism underlying MRONJ remains elusive, periodontitis is still contraindicated for bisphosphonates or Denosumab. These unmet needs call for the development of an anti-resorptive drug with no side effects.
Pharmaceutical industry has noticeably shifted drug development strategy from targeting small-molecule compounds to monoclonal antibodies, which are lab-made proteins that can bind to certain targets in the body (according to the NIH National Cancer Institute). The Kawai Lab excels in the generation of therapeutic monoclonal antibodies (mAbs). Dr. Kawai’s research team at NSU’s College of Dental Medicine has developed a unique method of generating mAbs toward virtually any kind of protein. Additional knowledge acquired from osteoimmunological research, including the identification of novel molecular targets, such as OC-STAMP and Semaphorin 4D, expressed on pathogenically activated osteoclasts, has now been translated into the development of novel monoclonal antibody (mAb) drugs for the treatment of periodontitis and other related bone-destructive diseases, such as osteoporosis, bone cancer metastasis and Rheumatoid arthritis.
This NIH funded project will aim to understand the molecular mechanisms underlying periodontitis and related systemic bone- destructive diseases and develop mAb drugs for those bone-destructive diseases based on acquired knowledge from basic osteoimmunological research. The final goal of this research will be extending life expectancy, as well as quality of life, by reducing the risk of developing systemic pathologies associated with periodontitis, as enumerated above.
