Yu Pilot Project Yu Pilot Project

Pilot project Awarded 2013

Hong Yu, M.D.
Research Assistant Professor
Craniofacial Biology

Role of sphingosine-1-phosphate signaling in periodontitis induced by A. actinomycetemcomitans Periodontitis is a set of bacteria-driven inflammatory diseases, which lead to progressive loss of alveolar bone and subsequently tooth loss. We and others have demonstrated that bacterial lipopolysaccharide or Aggregatibacter actinomycetemcomitans (Aa), theoral pathogen associated with localized aggressive periodontitis, induces the generation of the bioactive sphingolipid sphingosine-1-phosphate (S1P) by activating sphingosine kinase (Sphk). S1P binds to five G protein-coupled S1P receptors, initiating extracellular signaling pathways. S1P plays an important role in host immune responses, including regulation of immune cell chemotaxis and the release of cytokines and chemokines. Importantly, S1P signaling controls the trafficking of monocytes and macrophages (osteoclast precursors) from the circulation to the bone surface, where these cells can fuse into multinucleated osteoclasts, leading to bone resorption. Our preliminary studies show that treatment with FTY720, a functional antagonist of S1P receptors, inhibits the mRNA levels of IL-β, IL-6, TNF-α, and cyclooxygenase-2 (Cox-2) induced by Aa in Raw 264.7 cells, compared with controls. Treatment with FTY720 also suppresses osteoclastogenesis stimulated by Aa in mouse bone marrow cells compared with control. This pilot study will further study if down-regulation of S1P synthesis in Sphk1 knockout mice will have reduced proinflammatory responses and decreased alveolar bone loss compared with wild type mice in a periodontitis model induced by Aa.