A dominant function of p38 mitogen‐activated protein kinase signaling in receptor activator of nuclear factor‐κB ligand expression and osteoclastogenesis induction by Aggregatibacter actinomycetemcomitans and Escherichia coli lipopolysaccharide
- 24 August 2007
- journal article
- Published by Wiley in Journal of Periodontal Research
- Vol. 43 (2) , 201-211
- https://doi.org/10.1111/j.1600-0765.2007.01013.x
Abstract
Background and Objective: Lipopolysaccharide from gram‐negative bacteria is one of the microbial‐associated molecular patterns that initiate the immune/inflammatory response, leading to the tissue destruction observed in periodontitis. The aim of this study was to evaluate the role of the p38 mitogen‐activated protein kinase (MAPK) signaling pathway in lipopolysaccharide‐induced receptor activator of nuclear factor‐κB ligand (RANKL) expression by murine periodontal ligament cells.Material and Methods: Expression of RANKL and osteoprotegerin mRNA was studied by reverse transcription‐polymerase chain reaction upon stimulation with lipopolysaccharide from Escherichia coli and Aggregatibacter actinomycetemcomitans. The biochemical inhibitor SB203580 was used to evaluate the contribution of the p38 MAPK signaling pathway to lipopolysaccharide‐induced RANKL and osteoprotegerin expression. Stable cell lines expressing dominant‐negative forms of MAPK kinase (MKK)‐3 and MKK6 were generated to confirm the role of the p38 MAPK pathway. An osteoclastogenesis assay using a coculture model of the murine monocytic cell line RAW 264.7 was used to determine if osteoclast differentiation induced by lipopolysaccharide‐stimulated periodontal ligament was correlated with RANKL expression.Results: Inhibiting p38 MAPK prior to lipopolysaccharide stimulation resulted in a significant decrease of RANKL mRNA expression. Osteoprotegerin mRNA expression was not affected by lipopolysaccharide or p38 MAPK. Lipopolysaccharide‐stimulated periodontal ligament cells increased osteoclast differentiation, an effect that was completely blocked by osteoprotegerin and significantly decreased by inhibition of MKK3 and MKK6, upstream activators of p38 MAPK. Conditioned medium from murine periodontal ligament cultures did not increase osteoclast differentiation, indicating that periodontal ligament cells produced membrane‐bound RANKL.Conclusion: Lipopolysaccharide resulted in a significant increase of RANKL in periodontal ligament cells. The p38 MAPK pathway is required for lipopolysaccharide‐induced membrane‐bound RANKL expression in these cells.Keywords
This publication has 53 references indexed in Scilit:
- Mitogen‐activated protein kinases mediate interleukin‐1β‐induced receptor activator of nuclear factor‐κB ligand expression in human periodontal ligament cellsJournal of Periodontal Research, 2007
- B and T Lymphocytes Are the Primary Sources of RANKL in the Bone Resorptive Lesion of Periodontal DiseaseThe American Journal of Pathology, 2006
- Osteoclast differentiation requires TAK1 and MKK6 for NFATc1 induction and NF-κB transactivation by RANKLCell Death & Differentiation, 2006
- IL-1-induced receptor activator of NF-κB ligand in human periodontal ligament cells involves ERK-dependent PGE2 productionBone, 2005
- Regulatory Effects of Interleukin‐1β and Prostaglandin E2 on Expression of Receptor Activator of Nuclear Factor‐κB Ligand in Human Periodontal Ligament CellsThe Journal of Periodontology, 2004
- Parathyroid Hormone Stimulates Receptor Activator of NFκB Ligand and Inhibits Osteoprotegerin Expression via Protein Kinase A Activation of cAMP-response Element-binding ProteinJournal of Biological Chemistry, 2002
- Involvement of p38 Mitogen-activated Protein Kinase Signaling Pathway in Osteoclastogenesis Mediated by Receptor Activator of NF-κB Ligand (RANKL)Journal of Biological Chemistry, 2000
- Alkaline phosphatase induces the mineralization of sheets of collagen implanted subcutaneously in the rat.Journal of Clinical Investigation, 1992
- New attachment formation as the result of controlled tissue regenerationJournal of Clinical Periodontology, 1984
- On the Repair Potential of Periodontal TissuesThe Journal of Periodontology, 1976