TLR5, a novel mediator of innate immunity-induced osteoclastogenesis and bone loss

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-kappa B ligand (RANKL): osteoprotegerin ratio, with half-maximal stimulation at 0.01 mu g/ml. Flagellin enhanced Rankl mRNA in isolated osteoblasts by a myeloid differentiation primary response gene 88 and NF-kappa B-dependent mechanism. Injection of flagellin locally over skull bones in 5-wk-oldmice 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.

Henning, Petra,1974Gothenburg University,Göteborgs universitet,Centre for Bone and Arthritis Research(Swepub:gu)xhenpe (author)
Kindlund, Bert,1969Gothenburg University,Göteborgs universitet,Centre for Bone and Arthritis Research(Swepub:gu)xkinbe (author)
Lindholm, Catharina,1967Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Centre for Bone and Arthritis Research,Institute of Medicine, Department of Rheumatology and Inflammation Research(Swepub:gu)xlicat (author)
Lerner, Ulf HUmeå universitet,Gothenburg University,Göteborgs universitet,Centre for Bone and Arthritis Research,Institutionen för odontologi,Centre for Bone and Arthritis Research, Departments of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden(Swepub:umu)ulle0001 (author)
Umeå universitetInstitutionen för odontologi (creator_code:org_t)

By the author/editor: Kassem, Ali; Henning, Petra, ...; Kindlund, Bert, ...; Lindholm, Cathar ...; Lerner, Ulf H

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Endocrinology an ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Immunology in th ...

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