期刊
INTERNATIONAL IMMUNOPHARMACOLOGY
卷 88, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.intimp.2020.106870
关键词
Osteoarthritis; GPR17; Pranlukast; Oxidative stress; SOX-9; IRF-1; MMPs; JAK2/STAT1
资金
- Zhejiang medical and health science and technology project [2020KY347]
Osteoarthritis (OA) is a common joint disease affecting millions of elderly people worldwide. However, the mechanism of OA is complicated and remains poorly understood. Thus, a safe and effective therapeutic strategy has yet to be developed. G protein-coupled receptor 17 (GPR17) is an orphan receptor that is widely distributed in the central nervous system (CNS). GPR17 has become a target for the treatment of inflammation in brain diseases. In this study, we demonstrate that GPR17 is expressed in ATDC5 cells and is increased in response to TNF-alpha exposure. We also found that antagonism of GPR17 with pranlukast significantly inhibited oxidative stress by downregulating the intracellular level of reactive oxygen species (ROS) and increasing the activity of super oxide dismutase (SOD) against TNF-alpha. Interestingly, treatment with pranlukast prevented TNF-alpha-induced reduction of type II collagen. Additionally, knockdown of GPR17 with siRNA ameliorated TNF-alpha-induced loss of type II collagen, suggesting the importance of the role of GPR17 in mediating the impairment of type II collagen. Blockage of GPR17 with pranlukast suppressed the expression of matrix metalloproteinases 3 (MMP-3) and matrix metalloproteinases 13 (MMP-13), which contribute to the degradation of type II collagen. Pranlukast also prevented the activation of the JAK2/STAT1/IRF-1 signaling pathway, thereby suppressing the expression of pro-inflammatory cytokines and enzymes. Furthermore, pranlukast rescued TNF-alpha-induced reduced SOX-9 expression. Together, our data indicate that GPR17 might be a potential target for the treatment of OA.
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