title: TLR5, a novel mediator of innate immunity-induced osteoclastogenesis and bone loss.
abstract: Accumulating evidence points to the importance of the innate immune system in inflammation-induced bone loss in infectious and autoimmune diseases. TLRs are well known for being activated by ligands expressed by bacteria, viruses, and fungi. Recent findings indicate that also endogenous ligands in inflammatory processes are important, one being a TLR5 agonist present in synovial fluid from patients with rheumatoid arthritis (RA). We found that activation of TLR5 by its specific ligand, flagellin, caused robust osteoclast formation and bone loss in cultured mouse neonatal parietal bones dependent on increased receptor activator of NF-κB ligand (RANKL):osteoprotegerin ratio, with half-maximal stimulation at 0.01 μg/ml. Flagellin enhanced Rankl mRNA in isolated osteoblasts by a myeloid differentiation primary response gene 88 and NF-κB-dependent mechanism. Injection of flagellin locally over skull bones in 5-wk-old mice resulted in increased mRNA expression of Rankl and osteoclastic genes, robust osteoclast formation, and bone loss. The effects in vitro and in vivo were absent in Tlr5(-/-) mice. These data show that TLR5 is a novel activator of RANKL and osteoclast formation and, therefore, a potential key factor in inflammation-induced bone erosions in diseases like RA, reactive arthritis, and periodontitis. TLR5 might be a promising novel treatment target for prevention of inflammatory bone loss.
authors.affiliation: *Department of Molecular Periodontology, Umeå University, Umeå, Sweden; and Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, and Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Ali
authors.initials: A
authors.lastname: Kassem
authors.affiliation: *Department of Molecular Periodontology, Umeå University, Umeå, Sweden; and Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, and Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Petra
authors.initials: P
authors.lastname: Henning
authors.affiliation: *Department of Molecular Periodontology, Umeå University, Umeå, Sweden; and Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, and Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Bert
authors.initials: B
authors.lastname: Kindlund
authors.affiliation: *Department of Molecular Periodontology, Umeå University, Umeå, Sweden; and Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, and Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Catharina
authors.initials: C
authors.lastname: Lindholm
authors.affiliation: *Department of Molecular Periodontology, Umeå University, Umeå, Sweden; and Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, and Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden ulf.lerner@umu.se.
authors.forename: Ulf H
authors.initials: UH
authors.lastname: Lerner
mesh_terms: D000818:Animals; D001168:Arthritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007113:Immunity, Innate; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D010006:Osteoblasts / Q000276:immunology / Q000473:pathology; D010010:Osteoclasts / Q000276:immunology* / Q000473:pathology; D053244:Osteoprotegerin; D010518:Periodontitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D053245:RANK Ligand / Q000235:genetics / Q000276:immunology*; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000276:immunology*
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D053244:Osteoprotegerin; D053245:RANK Ligand; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D051198:Toll-Like Receptor 5
keywords: Toll-like receptors; bone resorption; flagellin; inflammation; osteoclasts