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: Satoshi Suzuki, Shinji Morimoto, Maki Fujishiro, Mikiko Kawasaki, Kunihiro Hayakawa, Tomoko Miyashita, Keigo Ikeda, Keiji Miyazawa, Mitsuaki Yanagida, Kenji Takamori, Hideoki Ogawa, Iwao Sekigawa, Yoshinari Takasaki
• Journal: Autoimmunity (Autoimmunity) Vol. 48 Issue 4 Pg. 251-8 (Jun 2015) ISSN: 1607-842X [Electronic] England
• PMID: 25352179 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• IGF1R protein, human
• Insulin-Like Growth Factor Binding Protein 3
• Insulin-Like Growth Factor Binding Proteins
• RANK Ligand
• Receptors, Somatomedin
• Somatomedins
• Insulin-Like Growth Factor I
• Macrophage Colony-Stimulating Factor
• C-Reactive Protein
• Receptor, IGF Type 1
• Matrix Metalloproteinase 3

Topics

• Adult
• Aged
• Antibodies, Monoclonal (pharmacology)
• Arthritis, Rheumatoid (blood, genetics, immunology, metabolism)
• C-Reactive Protein (metabolism)
• Cell Line
• Disease Progression
• Female
• Humans
• Insulin-Like Growth Factor Binding Protein 3 (blood, genetics, metabolism)
• Insulin-Like Growth Factor Binding Proteins (metabolism)
• Insulin-Like Growth Factor I (genetics, metabolism)
• Macrophage Colony-Stimulating Factor (metabolism)
• Macrophages (immunology, metabolism)
• Male
• Matrix Metalloproteinase 3 (metabolism)
• Middle Aged
• Neovascularization, Pathologic (genetics, metabolism)
• Osteoclasts (metabolism)
• RANK Ligand (metabolism)
• Receptor, IGF Type 1
• Receptors, Somatomedin (antagonists & inhibitors)
• Somatomedins (antagonists & inhibitors)
• Synovial Membrane (immunology, metabolism)