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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

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

Jin-Sil Park, Seung-Ki Kwok, Mi-Ae Lim, Eun-Kyung Kim, Jun-Geol Ryu, Sung-Min Kim, Hye-Joa Oh, Ji Hyeon Ju, Sung-Hwan Park, Ho-Youn Kim, Mi-La Cho

Arthritis Rheumatol. 2014 Apr;66(4):918-29.

PMID: 24757144

Abstract:

Objective:
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).
Methods:
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.
Results:
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.
Conclusion:
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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP111540002	STA-21		111540-00-2	Price

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