title: Inhibition of the insulin-like growth factor system is a potential therapy for rheumatoid arthritis.
abstract: OBJECTIVE
  We have shown that connective tissue growth factor (CTGF) plays an important role in the pathogenesis of rheumatoid arthritis (RA). Insulin-like growth factor binding proteins (IGFBPs) are modules of CTGF. IGFBPs bind IGF-I and IGF-II. IGF-I plays a role in the regulation of immunity, bone metabolism and inflammation. Therefore, we investigated how the IGF system is associated with RA disease progression.
  
  
  METHODS
  Serum samples were collected from RA patients. IGF-I and IGFBP-3 production were evaluated by enzyme-linked immunosorbent assay, real-time RT-PCR and indirect immunofluorescence microscopy. Osteoclastogenesis was evaluated using tartrate-resistant acid phosphatase staining, a bone resorption assay and osteoclast-specific enzyme production. Angiogenesis was examined by a tube formation assay using human umbilical vein endothelial cells.
  
  
  RESULTS
  The serum concentrations of IGFBP-3 in RA patients were greater than those in normal controls. IGF-I and IGFBP-3 were produced primarily by macrophages in the RA synovium. Furthermore, tumor necrosis factor-α could induce aberrant IGF-I and IGFBP-3 production in synovial fibroblasts. IGF-I and IGFBP-3 promoted the induction of osteoclast generation and morphological changes, in combination with M-colony stimulating factor and the receptor activator of NF-κB ligand. In addition, IGF-I and IGFBP-3 induced angiogenesis, as determined by the tube formation assay. These effects were neutralized by anti-IGF-IR monoclonal antibody (mAb).
  
  
  CONCLUSIONS
  These results indicate that aberrant IGF-I and IGFBP-3 production plays a role in abnormal osteoclastic activation and angiogenesis in RA. This work supports future clinical exploration of anti-IGF-IR mAb in drug repositioning as a new treatment for RA.
authors.affiliation: Institute for Environment and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Urayasu , Chiba , Japan .
authors.forename: Satoshi
authors.initials: S
authors.lastname: Suzuki
authors.forename: Shinji
authors.initials: S
authors.lastname: Morimoto
authors.forename: Maki
authors.initials: M
authors.lastname: Fujishiro
authors.forename: Mikiko
authors.initials: M
authors.lastname: Kawasaki
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Hayakawa
authors.forename: Tomoko
authors.initials: T
authors.lastname: Miyashita
authors.forename: Keigo
authors.initials: K
authors.lastname: Ikeda
authors.forename: Keiji
authors.initials: K
authors.lastname: Miyazawa
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Yanagida
authors.forename: Kenji
authors.initials: K
authors.lastname: Takamori
authors.forename: Hideoki
authors.initials: H
authors.lastname: Ogawa
authors.forename: Iwao
authors.initials: I
authors.lastname: Sekigawa
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Takasaki
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002097:C-Reactive Protein / Q000378:metabolism; D002460:Cell Line; D018450:Disease Progression; D005260:Female; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors; D013002:Somatomedins / Q000037:antagonists & inhibitors*; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; C000597236:IGF1R protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D053245:RANK Ligand; D017451:Receptors, Somatomedin; D013002:Somatomedins; D007334:Insulin-Like Growth Factor I; D016173:Macrophage Colony-Stimulating Factor; D002097:C-Reactive Protein; D017526:Receptor, IGF Type 1; D019278:Matrix Metalloproteinase 3
keywords: Anti-IGF-1R mAb; biologics; drug repositioning; insulin-like growth factor; rheumatoid arthritis