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.
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.


CONCLUSIONS
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.
Catholic University of Korea, Seoul, South Korea.
Jin-Sil
JS
Park
Seung-Ki
SK
Kwok
Mi-Ae
MA
Lim
Eun-Kyung
EK
Kim
Jun-Geol
JG
Ryu
Sung-Min
SM
Kim
Hye-Joa
HJ
Oh
Ji Hyeon
JH
Ju
Sung-Hwan
SH
Park
Ho-Youn
HY
Kim
Mi-La
ML
Cho
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D010010:Osteoclasts / Q000187:drug effects* / Q000473:pathology; D011083:Polycyclic Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000473:pathology; D058504:Th17 Cells / Q000187:drug effects* / Q000473:pathology
D011083:Polycyclic Compounds; C500947:STA-21; D050796:STAT3 Transcription Factor