title: Porphyromonas gingivalis Stimulates Bone Resorption by Enhancing RANKL (Receptor Activator of NF-κB Ligand) through Activation of Toll-like Receptor 2 in Osteoblasts.
abstract: Periodontitis has been associated with rheumatoid arthritis. In experimental arthritis, concomitant periodontitis caused by oral infection with Porphyromonas gingivalis enhances articular bone loss. The aim of this study was to investigate how lipopolysaccharide (LPS) from P. gingivalis stimulates bone resorption. The effects by LPS P. gingivalis and four other TLR2 ligands on bone resorption, osteoclast formation, and gene expression in wild type and Tlr2-deficient mice were assessed in ex vivo cultures of mouse parietal bones and in an in vivo model in which TLR2 agonists were injected subcutaneously over the skull bones. LPS P. gingivalis stimulated mineral release and matrix degradation in the parietal bone organ cultures by increasing differentiation and formation of mature osteoclasts, a response dependent on increased RANKL (receptor activator of NF-κB ligand). LPS P. gingivalis stimulated RANKL in parietal osteoblasts dependent on the presence of TLR2 and through a MyD88 and NF-κB-mediated mechanism. Similarly, the TLR2 agonists HKLM, FSL1, Pam2, and Pam3 stimulated RANKL in osteoblasts and parietal bone resorption. LPS P. gingivalis and Pam2 robustly enhanced osteoclast formation in periosteal/endosteal cell cultures by increasing RANKL. LPS P. gingivalis and Pam2 also up-regulated RANKL and osteoclastic genes in vivo, resulting in an increased number of periosteal osteoclasts and immense bone loss in wild type mice but not in Tlr2-deficient mice. These data demonstrate that LPS P. gingivalis stimulates periosteal osteoclast formation and bone resorption by stimulating RANKL in osteoblasts via TLR2. This effect might be important for periodontal bone loss and for the enhanced bone loss seen in rheumatoid arthritis patients with concomitant periodontal disease.
authors.affiliation: From the Department of Molecular Periodontology, Umeå University, 90187 Umeå, Sweden.
authors.forename: Ali
authors.initials: A
authors.lastname: Kassem
authors.affiliation: the Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition at Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Gothenburg, Sweden.
authors.forename: Petra
authors.initials: P
authors.lastname: Henning
authors.affiliation: From the Department of Molecular Periodontology, Umeå University, 90187 Umeå, Sweden.
authors.forename: Pernilla
authors.initials: P
authors.lastname: Lundberg
authors.affiliation: From the Department of Molecular Periodontology, Umeå University, 90187 Umeå, Sweden, the Department of Physiology and Pathology, Araraquara School of Dentistry, University Estudual Paulista (UNESP), Araraquara, Brazil 14801-903, and.
authors.forename: Pedro P C
authors.initials: PP
authors.lastname: Souza
authors.affiliation: the Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition at Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Gothenburg, Sweden, the Department of Rheumatology and Inflammation Research, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, 403 50 Gothenburg, Sweden.
authors.forename: Catharina
authors.initials: C
authors.lastname: Lindholm
authors.affiliation: From the Department of Molecular Periodontology, Umeå University, 90187 Umeå, Sweden, the Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition at Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Gothenburg, Sweden, ulf.lerner@umu.se.
authors.forename: Ulf H
authors.initials: UH
authors.lastname: Lerner
mesh_terms: D000818:Animals; D001862:Bone Resorption; D016207:Cytokines / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000378:metabolism*; D016966:Porphyromonas gingivalis / Q000502:physiology*; D011453:Prostaglandins / Q000502:physiology; D053245:RANK Ligand / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D011453:Prostaglandins; D053245:RANK Ligand; C493486:Tlr2 protein, mouse; C505689:Tnfsf11 protein, mouse; D051195:Toll-Like Receptor 2
keywords: bone; inflammation; innate immunity; osteoblast; osteoclast; toll-like receptor (TLR)