RRC ID 45355
Author Suzuki S, Morimoto S, Fujishiro M, Kawasaki M, Hayakawa K, Miyashita T, Ikeda K, Miyazawa K, Yanagida M, Takamori K, Ogawa H, Sekigawa I, Takasaki Y.
Title Inhibition of the insulin-like growth factor system is a potential therapy for rheumatoid arthritis.
Journal Autoimmunity
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.
Volume 48(4)
Pages 251-8
Published 2015-6-1
DOI 10.3109/08916934.2014.976631
PMID 25352179
MeSH Adult Aged Antibodies, Monoclonal / pharmacology Arthritis, Rheumatoid / blood Arthritis, Rheumatoid / genetics Arthritis, Rheumatoid / immunology Arthritis, Rheumatoid / metabolism* C-Reactive Protein / metabolism Cell Line Disease Progression Female Humans Insulin-Like Growth Factor Binding Protein 3 / blood Insulin-Like Growth Factor Binding Protein 3 / genetics Insulin-Like Growth Factor Binding Protein 3 / metabolism Insulin-Like Growth Factor Binding Proteins / metabolism Insulin-Like Growth Factor I / genetics Insulin-Like Growth Factor I / metabolism Macrophage Colony-Stimulating Factor / metabolism Macrophages / immunology Macrophages / metabolism Male Matrix Metalloproteinase 3 / metabolism Middle Aged Neovascularization, Pathologic / genetics Neovascularization, Pathologic / metabolism Osteoclasts / metabolism RANK Ligand / metabolism Receptors, Somatomedin / antagonists & inhibitors Somatomedins / antagonists & inhibitors* Synovial Membrane / immunology Synovial Membrane / metabolism
IF 2.403
Times Cited 12
Human and Animal Cells