Pathological role of osteoclast costimulation in arthritis-induced bone loss.
Abnormal T cell immune responses induce aberrant expression of inflammatory cytokines such as TNF-alpha, 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-alpha 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-kappaB (RANK). In fact, bone erosion and osteoporosis, but not inflammation, caused by aberrant TNF-alpha expression were ameliorated in mice deficient in Fc receptor common gamma subunit or beta(2)-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.
Ochi
Sae
S
Department of Cell Signaling, Graduate School, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan.
Shinohara
Masahiro
M
Sato
Kojiro
K
Gober
Hans-Jürgen
HJ
Koga
Takako
T
Kodama
Tatsuhiko
T
Takai
Toshiyuki
T
Miyasaka
Nobuyuki
N
Takayanagi
Hiroshi
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D005784:Gene Amplification / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D000069285:Infliximab; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000235:genetics; D010010:Osteoclasts / Q000166:cytology / Q000276:immunology / Q000473:pathology*; D010024:Osteoporosis / Q000235:genetics / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology
D000911:Antibodies, Monoclonal; D018836:Inflammation Mediators; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; C105948:Pira1 protein, mouse; C491377:Pira4 protein, mouse; C491375:Pira6 protein, mouse; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab