Project Title

Osteoimmunology of Retarded Bone Regeneration in Periodontitis

Principal Investigator/Project Director

Toshihisa Kawai

Colleges / Centers

College of Dental Medicine

Funder

U.S. DHHS NIH - National Institute of Dental and Craniofacial Research

Start Date

8-1-2020

Abstract

Retarded bone regeneration is characteristic to periodontitis. Even after successful conventional periodontal treatment, periodontal bone regeneration rarely, if ever, occurs, while molecular mechanism underlying retarded bone regeneration is largely unknown. This RO1 application proposes to exploit the osteoimmunological roles of osteoclast (OC)-specific cell membrane receptor, Osteoclast Stimulatory Transmembrane Protein (OCSTAMP) and Dendritic Cell-Specific Transmembrane Protein (DC-STAMP) in pathogenically dysregulated bone remodeling processes in periodontitis. During osteoclastic bone resorption, osteoblast (OB)-activation molecules, such as insulin-like growth factor (IGF), act as “coupling” factors released from demineralized bone matrix to ensure that the same amount of bone resorbed by OC is replaced by differentiation and activity of OB. Strong evidence suggests that this coupling mechanism is interrupted (‘uncoupled’) in periodontitis where pathogenic bone resorption exceeds reparative bone formation. Our preliminary results showed that P. gingivalis may be engaged in this pathogenic uncoupling processes. To date, the molecular mechanisms underlying ‘uncoupling’ in periodontitis remains elusive. A recent study reported that Semaphorin4D (Sema4D) produced by OC inhibits IGF-mediated osteogenesis by OB, thereby functioning as a novel uncoupling factor. The upstream molecular event(s) that induce(s)/upregulate(s) Sema4D expression by RANKL-activated osteoclast ptrecursors (OCp), as well as the mechanism of Sema4D action on OB in the context of periodontitis, are unknown. We found the ligand for OCSTAMP and binding of the ligand with OCSTAMP elicits signals for expression of uncoupling factor, Sema4D. Furthermore, periodontal pathogen, P. gingivalis, appears to upregulate the Sema4D production from OCp. Based on these preliminary findings, we hypothesized that pathogenic activation of OCSTAMP by its putative ligand inhibits osteogenesis by production of Sema4D in periodontitis. To test our hypothesis, the following Specific Aims are proposed: Aim 1: To identify the putative ligand for OC-STAMP, Aim 2: To assess the impact of OC-STAMP-activation on retarded periodontal bone regeneration in a mouse model of periodontitis induced by the combination of ligature attachment and P. gingivalis infection. This study will, for the first time, elucidate the pathologic osteoimmunological mechanism that interrupts new bone formation in alveolar bone affected by periodontitis, thus, representing a potential paradigm shift in the development of novel periodontitis therapies.

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