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Macrophage-Elicited Osteoclastogenesis in Response to Bacterial Stimulation Requires Toll-Like Receptor 2-Dependent Tumor Necrosis Factor-Alpha Production

Department of Medicine, Section of Molecular Medicine, Boston University School of Medicine, Boston, Massachusetts 02118,¹ Department of Periodontology, Unit of Translational Medicine, Course of Medical and Dental Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan,² Department of Conservative Dentistry, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8504, Japan,³ Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts 02118⁴

Received 10 September 2007/ Returned for modification 8 October 2007/ Accepted 29 October 2007

The receptor activator of NF-B ligand (RANKL) and the proinflammatory cytokines are believed to play important roles in osteoclastogenesis. We recently reported that the innate immune recognition receptor, Toll-like receptor 2 (TLR2), is crucial for inflammatory bone loss in response to infection by Porphyromonas gingivalis, the primary organism associated with chronic inflammatory periodontal disease. However, the contribution of macrophage-expressed TLRs to osteoclastogenesis has not been defined. In this study, we defined a requirement for TLR2 in tumor necrosis factor-alpha (TNF-)-elicited osteoclastogenesis in response to exposure to P. gingivalis. Culture supernatant (CS) fluids from P. gingivalis-stimulated macrophages induced bone marrow macrophage-derived osteoclastogenesis. This activity was dependent on TNF- and occurred independently of RANKL, interleukin-1β (IL-1β), and IL-6. CS fluids from P. gingivalis-stimulated TLR2^–/– macrophages failed to express TNF-, and these fluids induced significantly less osteoclast formation compared with that of the wild-type or the TLR4^–/– macrophages. In addition, P. gingivalis exposure induced up-regulation of TLR2 expression on the cell surface of macrophages, which was demonstrated to functionally react to reexposure to P. gingivalis, as measured by a further increase in TNF- production. These results demonstrate that macrophage-dependent TLR2 signaling is crucial for TNF--dependent/RANKL-independent osteoclastogenesis in response to P. gingivalis infection. Furthermore, the ability of P. gingivalis to induce the cell surface expression of TLR2 may contribute to the chronic inflammatory state induced by this pathogen.

Published ahead of print on 12 November 2007.

Editor: A. J. Bäumler