Friday, April 26, 2024
4/26/2024
Project Summary Excessive activity of osteoclasts (OC), the body's sole bone resorbing cells, is a major characteristic of pathogenic bone loss in periodontitis. Although a great deal is known about the process of OC differentiation, the identity of OC precursors (OCP) in vivo, and their role in periodontitis remain scarce, especially in aging where the extent of bone loss is increased. Recent studies have identified a cell cycle-arrested quiescent OCP present in very low numbers. These cells are receptor activator of NF-¿B (RANK)-positive and express colony- stimulating factor-1 receptor (c-fms) at various levels, but scarcely express monocyte/macrophage/ granulocyte markers. Using in vivo mouse models, we have shown that infection with the periodontal-associated pathogen Porphyromonas gingivalis (Pg) induces the expansion of an earlier stage c-fms+RANK- OCP (eOCP) and the more advanced stage RANK+ OCP (rOCP) in bone marrow and spleen. In addition, eOCP and rOCP potently suppress CD4+ T cell proliferation in vitro, highlighting an important role of OCP in immune regulation. Moreover, compared to young mice, old mice show increased periodontal bone loss, as well as increased OCP frequency and osteoclastogenic potential, suggesting that increased OCP pool underlies host susceptibility to periodontal bone loss in aging. Based on our preliminary studies and published work, we hypothesize that Pg infection results in the expansion of OCP that can be shunted toward OC formation and bone loss at the infection/inflammation sites, while at the same time dampen host immune responses, which is beneficial for the persistence of infection and maintenance of chronic inflammation. We will test our hypothesis by pursuing two specific aims: 1) Delineate the regulation of OCP following Pg infection; 2) Determine the effect of OCP on host immune responses and bone loss in vivo to Pg infection. Our proposed studies will provide novel and significant insight into the pathogenesis of Pg infection and periodontitis leading to the potential development of targeted therapeutics for inflammatory bone loss diseases.
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