Periodontopathic bacterial infection is closely associated with the inflammatory destruction of alveolar bone in periodontitis by both direct and indirect effects on osteoclast (OC) differentiation. However, the precise mechanisms by which pathogenic bacteria regulate OC differentiation still remain controversial. The receptor activator of NF-?B ligand (RANKL) and its receptor RANK are the key regulators for bone remodeling and for the activation of OC. Porphyromonas gingivalis (Pg) is considered a major etiologic agent of periodontitis. The ability of the host's immune system to sense, recognize and respond to Pg is largely mediated by the innate immune system via Toll-like receptors (TLR) 2 and 4. Our preliminary studies have demonstrated in vitro that Pg differentially modulates RANKL-induced OC formation by inhibiting OC differentiation from non-committed precursors and by potentiating OC differentiation from RANKL-committed cells. Furthermore, Pg utilizes TLR2/MyD88 to inhibit osteoclastogenesis by suppressing RANKL-induced c-Fos and NFATc1 activity. Most importantly, RANKL-committed OC precursors become refractory to Pg/TLR/cytokine signaling. These preliminary studies are the first to characterize a biphasic role of Pg on RANKL-induced osteoclastogenesis, and have identified a crosstalk between TLR and RANK signaling pathways. The overall goal of this study is to further delineate the molecular mechanisms of TLR-mediated regulation of osteoclastogenesis in the context of Pg infection. Based on our preliminary studies and published work, we hypothesize that the functional interaction between TLR and RANK signaling, namely a lack of OC formation from non-committed precursor cells by Pg-mediated TLR activation and a lack of cytokine response to TLR stimulation by RANKL-committed cells, plays an essential role in Pg-induced bone loss in vivo. We will test this hypothesis by pursuing two specific aims: 1. Delineate the molecular mechanisms underlying the functional interaction between TLR and RANK signaling during RANKL-induced osteoclastogenesis upon Pg stimulation in vitro;2. Determine the involvement of TLR2/MyD88 in Pg-induced bone loss in an in vivo mouse model. The identification and characterization of the functional interaction between bacterial infection and OC differentiation i critical for an understanding of periodontal disease pathogenesis. Furthermore, insight into the molecular mechanisms by which TLR signaling regulates osteoclastogenesis has potential to define novel therapeutic targets for prevention and treatment of the disease.
Diseases characterized by inflammation and the loss of bone, like periodontitis have debilitating and costly consequences to the population at large. Therefore, understanding the mechanisms regulating inflammation and osteoclastogenesis is a critical endeavor for the development of therapeutic interventions for the treatment of inflammatory bone loss diseases.
|Chen, Zhihong; Su, Lingkai; Xu, Qingan et al. (2015) IL-1R/TLR2 through MyD88 Divergently Modulates Osteoclastogenesis through Regulation of Nuclear Factor of Activated T Cells c1 (NFATc1) and B Lymphocyte-induced Maturation Protein-1 (Blimp1). J Biol Chem 290:30163-74|