Regeneration of periodontal tissues including formation of new alveolar bone, and generation of new connective tissue attachment have been the ultimate goals of periodontal research and therapy since the 1980ies. Here we have identified the highly selective SETD7 methyltransferase activity inhibitor (R)-PFI-2 (PFI-2) as a powerful small molecule modulator that ameliorated the severity of periodontal inflammation and significantly promoted new alveolar bone formation, new cementum formation, and periodontal ligament re-attachment. When PFI-2 was applied to periodontal defects in our rodent model, there was a substantial 1.7-fold increase in alveolar bone height equivalent to a 3 mm gain in vertical bone of attachment levels in humans when compared to controls. These preliminary data indicate that PFI-2 might represent a new answer to the quest for periodontal regeneration and a molecule capable of tipping the periodontal homeostasis balance in favor of the anabolic side. Explaining the mechanisms by which PFI-2 affects periodontal stem cell function, our preliminary data have demonstrated that PFI-2 treatment increased YAP1 nuclear translocation and downstream gene expression, suggesting that PFI-2 affects periodontal gene expression under inflammatory conditions through a novel pathway that includes the methyltransferase SETD7 and the Hippo pathway member YAP1. Based on these exciting preliminary data we have now hypothesized that PFI-2 upregulates YAP1 target gene expression through nuclear translocation, resulting in improved periodontal progenitor proliferation and differentiation, and reduced periodontal bone loss under inflammatory conditions. We anticipate that these studies will result in the development of novel small molecule-based therapeutics for the treatment of periodontal disease and to combat the associated loss of periodontal tissue that will aid the practicing periodontist.

Public Health Relevance

A New Treatment for Gum Diseases Inflammation of the gums is painful and can lead to tooth loss if not treated in a timely manner. Here we have developed a novel treatment for gum diseases in form of the PFI-2 small molecule probe, that promises to return disease periodontal tissues to their healthy state. Application of this molecule to cure the diseased gums will help to reduce gum disease and reduce the bone loss associated with it. As a result of this treatment, the chances to loose teeth will also be reduced. If we receive support for our application, we will be able to develop this new treatment for gum diseases and help millions of patients who have to see the dentist because their gums are bleeding.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Oral, Dental and Craniofacial Sciences Study Section (ODCS)
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Wan, Jason
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Texas A&M University
Schools of Dentistry/Oral Hygn
College Station
United States
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