Pathological role of osteoclast costimulation in arthritis-induced bone loss

• Published in: Proceedings of the National Academy of Sciences - PNAS 2007-07, Vol.104 (27), p.11394-11399
• Main Authors: Ochi, Sae, Shinohara, Masahiro, Sato, Kojiro, Gober, Hans-Jürgen, Koga, Takako, Kodama, Tatsuhiko, Takai, Toshiyuki, Miyasaka, Nobuyuki, Takayanagi, Hiroshi
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - administration & dosage; Arthritis; Arthritis, Experimental - genetics; Arthritis, Experimental - immunology; Arthritis, Experimental - pathology; Arthritis, Experimental - therapy; Biological Sciences; Bones; Cell Differentiation - genetics; Cell Differentiation - immunology; Cells; Cytokines; Gene Amplification - immunology; Gene expression; Inflammation; Inflammation Mediators - immunology; Inflammation Mediators - metabolism; Inflammation Mediators - physiology; Inflammatory diseases; Infliximab; Ligands; Mice; Mice, Knockout; Mice, Transgenic; Molecules; NFATC Transcription Factors - genetics; Osteoclasts; Osteoclasts - cytology; Osteoclasts - immunology; Osteoclasts - pathology; Osteoporosis - genetics; Osteoporosis - immunology; Osteoporosis - pathology; Osteoporosis - therapy; Pathology; Receptors; Receptors, Immunologic - biosynthesis; Receptors, Immunologic - genetics; Receptors, Immunologic - physiology; Stem cells; T lymphocytes; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - physiology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0701971104

Abnormal T cell immune responses induce aberrant expression of inflammatory cytokines such as TNF-α, leading to osteoclastmediated bone erosion and osteoporosis in autoimmune arthritis. However, the mechanism underlying enhanced osteoclastogenesis in arthritis is not completely understood. Here we show that TNF-α contributes to inflammatory bone loss by enhancing the osteoclastogenic potential of osteoclast precursor cells through inducing paired Ig-like receptor-A (PIR-A), a costimulatory receptor for receptor activator of NF-κB (RANK). In fact, bone erosion and osteoporosis, but not inflammation, caused by aberrant TNF-α expression were ameliorated in mice deficient in Fc receptor common γ subunit or β₂-microglobulin, in which the expression of PIR-As and PIR-A ligands is impaired, respectively. These results establish the pathological role of costimulatory receptors for RANK in bone loss in arthritis and may provide a molecular basis for the future therapy of inflammatory diseases.