Role of OC-STAMP expressed on human osteoclasts in periodontitis

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This application for “Administrative Supplements to Recognize Excellence in DEIA mentorship (NOT-OD-23- 002)” to the active R01 grant project (DE029709), entitled, “Role of OC-STAMP expressed on human osteoclasts in periodontitis”, proposes to develop a humanized mouse model of periodontitis to study the possible pathogenic roles of OC-STAMP expressed on human osteoclasts (OCs) in periodontitis lesion. The NSG-SGM3-W41 mouse strain which is one of the most advanced immunodeficient mouse strains developed by Dr. Shultz at the Jackson Laboratory allows us to reconstruct the full immune compartments containing both myeloid and lymphoid cell populations following transplantation of human hematopoietic stem cells (hHSC) without conditioning by irradiation. Recent study using humanized NSG mice showed that human OCs which are monocyte linage cells derived from hHSCs can be detected in the surrogate body of NSG mice. Relevant to parent R01 grant project, we preliminary discovered that, P. gingivalis (Pg), the keystone pathogen of periodontitis, increases the expression of OC-STAMP by human OC precursor cells. Since mouse lymphocytes don’t mount pathogenic immune response to orally inoculated Pg, it is argued that human lymphocytes which are under the control of mouse MHC-II in the humanized mice may not produce sufficient amount of RANKL to cause periodontitis in the humanized immunodeficient mice. However, we found that periodontal bone loss and local production of RANKL can be induced by ligature attachment to RAG1 immunodeficient mice, indicating that lymphocytes are not the major cellular source of RANKL in ligature-induced mouse periodontitis. Furthermore, because OC-STAMP is distinctively expressed by OCs and OC precursors, but not other lymphocytes derived from hHSCs, the anti-OC-STAMP Ab administered to humanized mice are expected to act on only human OCs. We hypothesize that Pg-dependently upregulated OC-STAMP expression by human OCs may promote the pathogenic bone resorption in the humanized mice indicative of periodontitis. This hypothesis will be tested by following two aims: 1) To examine the effects of anti-OCST Ab on the onset and progression of periodontitis induced in humanized mice with or without Pg inoculation, and 2) to determine the ligand of human OC-STAMP that promote the RANKL-induced OC-genesis in human OCs. Upon successful completion of this proposed study, it is anticipated that the roles of human OC-STAMP expressed by human OCs in periodontitis will be determined. This humanized mouse model of periodontitis would provide a platform for understanding the physiological context of molecules expressed on human OCS.