Kinase inhibitors of the IGF-1R as a potential therapeutic agent for rheumatoid arthritis

Abstract

We have previously shown that the inhibition of connective tissue growth factor (CTGF) is a potential therapeutic strategy against rheumatoid arthritis (RA). CTGF consists of four distinct modules, including the insulin-like growth factor binding protein (IGFBP). In serum, insulin-like growth factors (IGFs) bind IGFBPs, interact with the IGF-1 receptor (IGF-1 R), and regulate anabolic effects and bone metabolism. We investigated the correlation between IGF-1 and the pathogenesis of RA, and the inhibitory effect on osteoclastogenesis and angiogenesis of the small molecular weight kinase inhibitor of the IGF-1 R, NVP-AEW541, against pathogenesis of RA in vitro. Cell proliferation was evaluated by cell count and immunoblotting. The expression of IGF-1 and IGF-1 R was evaluated by RT-PCR. Osteoclastogenesis was evaluated using tartrate-resistant acid phosphatase staining, a bone resorption assay, and osteoclast-specific enzyme production. Angiogenesis was evaluated by a tube formation assay using human umbilical vein endothelial cells (HUVECs). The proliferation of MH7A cells was found to be inhibited in the presence of NVP-AEW541, and the phosphorylation of extracellular signal-regulated kinase (ERK) and Akt was downregulated in MH7A cells. IGF-1 and IGF-1 R mRNA expression levels were upregulated during formation of M-colony stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL)-mediated osteoclast formation. Moreover, osteoclastogenesis was suppressed in the presence of NVP-AEW541. The formation of the tubular network was enhanced by IGF-1, and this effect was neutralized by NVP-ARE541. Our findings suggest that NVP-AEW541 may be utilized as a potential therapeutic agent in the treatment of RA.

Keywords:

• Rheumatoid arthritis
• insulin-like growth factor system
• IGF-1R tyrosine kinase inhibitor
• small molecular-weight compound
• osteoclastogenesis

Acknowledgments

We are grateful to Ms. Fumi Kawabata and Ms. Kazumi Goto for providing secretarial assistance.

Disclosure statement

The authors report no conflicts of interest. This study supported by in part by a Grant-in-Aide from MEXT (Ministry of Education, Culture, Sports, Science and Technology) Supported Program for the Strategic Research Foundation at Private University [grant number S1311011].

Notes on contributors

Hiroshi Tsusima is a graduate student of the Institute for Environment and Gender Specific Medicine. His research interests focus on clinical immunology of Rheumatology.

Shinji Morimoto is an associate professor of the Department of Internal Medicine and Rheumatology, Juntendo University Urayasu Hospital. His works focus on clinical immunology of Rheumatology, especially Systemic Lupus Erythematosus. He also teaches graduate students at the Institute for Environment and Gender Specific Medicine.

Maki Fujishito is a technician of the the Institute for Environment and Gender Specific Medicine. She is a expert of immunologic experiment.

Yuko Yoshida is a postdoctoral fellow of the the Institute for Environment and Gender Specific Medicine. Her research interests focus on epigenetics on atopic disease.

Kunihiro Hayakawa is a postdoctoral fellow of the Institute for Environment and Gender Specific Medicine. Former, he worked at department of pathology, International Medical Center of Japan. Now His works focus on relation between lipid and immunology.

Takuya Hirai is a graduate student of the Institute for Environment and Gender Specific Medicine. His research interests focus on clinical immunology of Rheumatology, especially pathogenesis on relation between microRNA and myositis.

Tomoko Miyashita is an assistant professor of the Department of Internal Medicine and Rheumatology, Juntendo University Urayasu Hospital. Her research interests focus on clinical feature of lupus nephritis.

Keigo Ikeda is an assistant professor of the Department of Internal Medicine and Rheumatology, Juntendo University Urayasu Hospital. His research interests focus on clinical immunology of Rheumatology, especially the role of janus kinase inhibitor on lupus model mice.

Ken Yamaji is an associate professor of the Department of Internal Medicine and Rheumatology, Juntendo University Hospital. He is a chief of plasma exchange section.

Kenji Takamori is a director of the Institute for Environment and Gender Specific Medicine. His specialty is biochemistry and dermatology.

Yoshinari Takasaki is a director of Juntndo University Koshigaya Hospital. His major is Rheumatology. His research interests focus on the role of anti-nucleolar antibody on rheumatic disease.

Iwao Sekigawa is a professor of the Department of Internal Medicine and Rheumatology, Juntendo University Urayasu Hospital, and vice-president of the Institute for Environment and Gender Specific Medicine. His research interests focus on epigenetics of Rheumatic disease.

Naoto Tamura is a professor of the Department of Internal Medicine and Rheumatology, Juntendo University Hospital. His research interests focus on clinical immunology, especially of rheumatoid arthritis and spondylarthritis.

Additional information

Funding

This study supported by in part by a Grant-in-Aide from MEXT (Ministry of Education, Culture, Sports, Science and Technology) Supported Program for the Strategic Research Foundation at Private University [grant number S1311011].