Involvement of Cot/Tp12 in Bone Loss during Periodontitis

Abstract

Periodontitis causes resorption of alveolar bone, in which RANKL induces osteoclastogenesis. The binding of lipopolysaccharide to Toll-like receptors causes phosphorylation of Cot/Tp12 to activate the MAPK cascade. Previous in vitro studies showed that Cot/Tp12 was essential for the induction of RANKL expression by lipopolysaccharide. In this study, we examined whether Cot/Tp12 deficiency reduced the progression of alveolar bone loss and osteoclastogenesis during experimental periodontitis. We found that the extent of alveolar bone loss and osteoclastogenesis induced by ligature-induced periodontitis was decreased in Cot/Tp12-deficient mice. In addition, reduction of RANKL expression was observed in periodontal tissues of Cot/Tp12-deficient mice with experimental periodontitis. Furthermore, we found that Cot/Tp12 was involved in the induction of TNF-alpha mRNA expression in gingiva of mice with experimental periodontitis. Our observations suggested that Cot/Tp12 is essential for the progression of alveolar bone loss and osteoclastogenesis in periodontal tissue during experimental periodontitis mediated through increased RANKL expression.

LPS‐induced chemokine expression in both MyD88‐dependent and ‐independent manners is regulated by Cot/Tpl2‐ERK axis in macrophages

“…In summary, this study has shown that the role of MyD88 and Cot/Tpl2 in LPS‐induced chemokine expression in macrophages considerably varies depending on the kind of chemokine. Cot/Tpl2 in macrophages has been reported to regulate LPS‐induced cytokine expression in positive (TNF‐α and IL‐23) or negative (IL‐12) manner [18–21]. This present study further indicated that Cot/Tpl2 directly regulates transcription of various chemokines in LPS‐stimulated macrophages.…”

“…We and others have previously demonstrated that Cot/Tpl2 is indispensable for the LPS-induced activation of ERKs in macrophages, dendritic cells, and osteoblasts [16][17][18][19]. Lack of ERK activation in cot/tpl2 À/À macrophages results in impaired secretion of tumor necrosis factor (TNF) a and IL-23, along with the increased secretion of IL-12, in response to LPS [18][19][20][21].…”

Lipopolysaccharide and Hypoxia‐Induced HIF‐1 Activation in Human Gingival Fibroblasts

“…LPS signaling through pattern recognition receptors, such as Toll‐like receptor 4 (TLR4), triggers a cascade of intracellular events leading to the activation of intracellular transcription factors (e.g., nuclear factor κB), resulting in the production of proinflammatory cytokines 1 . LPS have been found to cause the breakdown of connective tissue and resorption of alveolar bone through the interaction with the host cells, including gingival fibroblasts 2,3 …”

“…1 LPS have been found to cause the breakdown of connective tissue and resorption of alveolar bone through the interaction with the host cells, including gingival fibroblasts. 2,3 The fibroblast is the most abundant cell type in gingival connective tissues. Fibroblasts play a crucial role in maintaining, repairing, and remodeling of the extracellular matrix necessary for connective tissue homeostasis.…”

Role of PTPα in the Destruction of Periodontal Connective Tissues

“…As the levels of several inflammatory cytokines, including IL-1β [24] and TNF-α [25] are strongly increased in ligature-induced periodontitis in mice, as well in rats [26], we determined whether PTPα regulates inflammation-mediated destruction of periodontal tissues by placement of silk ligatures around the necks of molar teeth to induce periodontitis [27], [28] using wild type (PTPα +/+ ) or knock out (PTPα −/− ) mice. First the genotype of mice was confirmed by PCR analysis of tail clips using primers that recognize the insert in the null genotype.…”