Drs. J.-S. Park and Kwok contributed equally to this work.
STA-21, a Promising STAT-3 Inhibitor That Reciprocally Regulates Th17 and Treg Cells, Inhibits Osteoclastogenesis in Mice and Humans and Alleviates Autoimmune Inflammation in an Experimental Model of Rheumatoid Arthritis
Version of Record online: 28 MAR 2014
Copyright © 2014 by the American College of Rheumatology
Arthritis & Rheumatology
Volume 66, Issue 4, pages 918–929, April 2014
How to Cite
Park, J.-S., Kwok, S.-K., Lim, M.-A., Kim, E.-K., Ryu, J.-G., Kim, S.-M., Oh, H.-J., Ju, J. H., Park, S.-H., Kim, H.-Y. and Cho, M.-L. (2014), STA-21, a Promising STAT-3 Inhibitor That Reciprocally Regulates Th17 and Treg Cells, Inhibits Osteoclastogenesis in Mice and Humans and Alleviates Autoimmune Inflammation in an Experimental Model of Rheumatoid Arthritis. Arthritis & Rheumatology, 66: 918–929. doi: 10.1002/art.38305
- Issue online: 28 MAR 2014
- Version of Record online: 28 MAR 2014
- Accepted manuscript online: 10 DEC 2013 02:30PM EST
- Manuscript Accepted: 26 NOV 2013
- Manuscript Received: 25 JAN 2013
- Ministry of Education, Science, and Technology, Republic of Korea through funding to the National Research Foundation of Korea (Basic Science Research Program. Grant Number: 2009-0081791
- Ministry for Health, Welfare, and Family Affairs, Republic of Korea (Korean Health Technology R&D Project). Grant Number: A092258
To investigate the impact of STA-21, a promising STAT-3 inhibitor, on the development and progression of inflammatory arthritis and to determine the possible mechanisms by which STA-21 has antiarthritic effects in interleukin-1 receptor antagonist–knockout (IL-1Ra–KO) mice, an animal model of rheumatoid arthritis (RA).
IL-1Ra–KO mice were treated with intraperitoneal injections of STA-21 (0.5 mg/kg) or vehicle 3 times per week for 3 weeks. The mouse joints were assessed for clinical and histologic features of inflammatory arthritis. CD4+CD25+FoxP3+ Treg cells and CD4+IL-17+ cells were defined. Human peripheral blood mononuclear cell–derived monocytes or mouse bone marrow–derived monocyte/macrophage (BMM) cells were cultured in the presence of macrophage colony-stimulating factor alone or together with RANKL and various concentrations of STA-21, followed by staining of the cells for tartrate-resistant acid phosphatase activity to determine osteoclast formation.
STA-21 suppressed inflammatory arthritis in IL-1Ra–KO mice. The proportion of Th17 cells was decreased and the proportion of Treg cells expressing FoxP3 was markedly increased in the spleens of STA-21–treated mice. Adoptive transfer of CD4+CD25+ T cells obtained from STA-21–treated IL-1Ra–KO mice markedly suppressed inflammatory arthritis. In vitro treatment with STA-21 induced the expression of FoxP3 and repressed IL-17 expression in both mouse and human CD4+ T cells. Moreover, STA-21 prevented both mouse BMM cells and human monocytes from differentiating into osteoclasts in vitro.
STA-21 improved the clinical course of arthritis in IL-1Ra–KO mice. It increased not only the number of Treg cells but also the function of the Treg cells. It also suppressed Th17 cells and osteoclast formation. These data suggest that STA-21 might be an effective treatment for patients with RA.