title: Reciprocal activation of CD4+ T cells and synovial fibroblasts by stromal cell-derived factor 1 promotes RANKL expression and osteoclastogenesis in rheumatoid arthritis.
abstract: OBJECTIVE
  Stromal cell-derived factor 1 (SDF-1) is a chemokine that is involved in the bone-destructive process in rheumatoid arthritis (RA) and bony metastasis in malignancy. This study was undertaken to determine the role and mechanism of SDF-1 in RA-associated osteoclastogenesis.
  
  
  METHODS
  The expression of SDF-1, tumor necrosis factor α (TNFα), and RANKL in RA synovial tissue was analyzed using confocal microscopy. After synovial fibroblasts and CD4+ T cells were treated with SDF-1, RANKL messenger RNA expression was determined by real-time and reverse transcription polymerase chain reaction. Osteoclastogenesis was assessed by counting tartrate-resistant acid phosphatase-positive multinucleated cells in CD14+ monocytes cultured with SDF-1 in the presence of anticytokine antibodies or signal inhibitors and in monocytes cocultured with SDF-1-pretreated synovial fibroblasts and CD4+ T cells.
  
  
  RESULTS
  RANKL, TNFα, and SDF-1 were coexpressed in the lining and sublining of RA synovium. SDF-1 stimulated RANKL expression in RA synovial fibroblasts and CD4+ T cells, and TNFα inhibition reduced this stimulation. When monocytes isolated from human peripheral blood were cultured with SDF-1, they were differentiated into osteoclasts in the absence of RANKL. Monocytes were also differentiated into osteoclasts when they were cocultured with SDF-1-pretreated synovial fibroblasts or CD4+T cells; however, this osteoclastogenesis was reduced by TNFα inhibition.
  
  
  CONCLUSIONS
  Our findings indicate that SDF-1 induces osteoclastogenesis directly and indirectly via up-regulating RANKL expression in RA synovial fibroblasts and CD4+ T cells, and that this is mediated by TNFα. The axis of SDF-1 and RANKL is a potential therapeutic target for RA-associated bone destruction.
authors.affiliation: Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, South Korea.
authors.forename: Hae-Rim
authors.initials: HR
authors.lastname: Kim
authors.forename: Kyoung-Woon
authors.initials: KW
authors.lastname: Kim
authors.forename: Bo-Mi
authors.initials: BM
authors.lastname: Kim
authors.forename: Hong-Geun
authors.initials: HG
authors.lastname: Jung
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
authors.forename: Sang-Heon
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism* / Q000601:surgery; D019645:Arthroplasty, Replacement, Knee; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007719:Knee Joint / Q000187:drug effects / Q000378:metabolism / Q000601:surgery; D008297:Male; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000235:genetics / Q000378:metabolism / Q000601:surgery; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D054377:Chemokine CXCL12; D053245:RANK Ligand; D014409:Tumor Necrosis Factor-alpha