Reference - Detail
|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.|
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.
|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|
|Human and Animal Cells|