期刊
JOURNAL OF ORTHOPAEDIC TRANSLATION
卷 29, 期 -, 页码 89-99出版社
ELSEVIER
DOI: 10.1016/j.jot.2021.05.001
关键词
Andrographolide; TNFR2 trafficking; NF-kappa B; Synovial inflammation; OA treatment
类别
资金
- National Key R&D Program of China [2018YFC1105904]
- Key Program of NSFC, China [81730067]
- National Science Foundation of China [81772335, 81941009, 81802196]
- Natural Science Foundation of Jiangsu Province, China [BK20180127]
- Jiangsu Provincial Key Medical Talent Foundation, China
- Six Talent Peaks Project of Jiangsu Province, China [WSW-079]
Andro can suppress synovial inflammation and OA progression by regulating TNFR2 trafficking and degradation, providing a potential novel therapeutic approach for OA and pain management.
Background: Synovial inflammation plays a major role in the pathogenesis of osteoarthritis (OA). This study investigated the effect of andrographolide (Andro) on synovial inflammation mediated by tumor necrosis factoralpha receptor 2 (TNFR2) trafficking and its utility in attenuating OA progression. Methods: Knee joints were harvested from rats subjected to radial transection of the medial collateral ligament (MCLT) and medial meniscus (MMT) to examine the effect of Andro on synovial inflammation and OA progression. Quantitative real-time polymerase chain reaction was used to evaluate the expression of inflammatory factors in primary fibroblast-like synoviocytes (FLSs) after Andro treatment in vitro. The mechanism underlying Andro-mediated regulation of TNFR2 distribution and nuclear factor-kappa B (NF-kappa B) expression was verified using endosome maturation inhibitor hydroxychloroquine (HCQ) through flow cytometry, immunofluorescence, and western blot analysis. Results: Andro treatment was found to reduce synovial inflammation and OA progression in vivo. Furthermore, a decrease in pain hypersensitivity and dorsal horn neuron activation was observed after treatment. Andro also downregulated the expression of inflammatory mediators and TNFR2 in FLSs. TNFR2 is crucial for the activation of the NF-kappa B signaling pathway, and Andro-induced degradation of TNFR2 was associated with lysosomal function, which in turn, reduced the downstream phosphorylation of p65 in the NF-kappa B signaling pathway. Conclusions: Andro could suppress synovial inflammation via regulation of TNFR2 trafficking and degradation. This also suggests it could be a potential treatment for the prevention of synovial inflammation and OA progression. The translational potential of this article: This study provides strong evidence that Andro reduces NF-kappa B activation and inflammatory responses in OA FLSs via regulation of TNFR2 trafficking. The inhibition of TNFR2 and Andro could be a novel therapeutic approach for OA and pain management.
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