Andrographolide attenuates synovial inflammation of osteoarthritis by interacting with tumor necrosis factor receptor 2 trafficking in a rat model

Rongliang Wang; Jiawei Li; Xingquan Xu; Jia Xu; Huiming Jiang; Zhongyang Lv; Rui Wu; Ziying Sun; Wenjie Guo; Yang Sun; Shiro Ikegawa; Qing Jiang; Dongquan Shi

doi:10.1016/j.jot.2021.05.001

Andrographolide attenuates synovial inflammation of osteoarthritis by interacting with tumor necrosis factor receptor 2 trafficking in a rat model

J Orthop Translat. 2021 May 24:29:89-99. doi: 10.1016/j.jot.2021.05.001. eCollection 2021 Jul.

Authors

Rongliang Wang^{1

2}, Jiawei Li^{1

2}, Xingquan Xu^{1

2}, Jia Xu^{2

3}, Huiming Jiang^{2

4}, Zhongyang Lv^{1

2}, Rui Wu^{1

2}, Ziying Sun^{1

2}, Wenjie Guo⁵, Yang Sun⁵, Shiro Ikegawa^{1

6}, Qing Jiang^{1

2

3

4}, Dongquan Shi^{1

2

3

4}

Affiliations

¹ State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, PR China.
² Joint Research Center for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing, Jiangsu, 210093, PR China.
³ Drum Tower of Clinical Medicine, Nanjing Medical University, Nanjing, 210008, Jiangsu, PR China.
⁴ Department of Sports Medicine and Joint Surgery, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, 210000, PR China.
⁵ State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210093, PR China.
⁶ Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Science (IMS, RIKEN), Tokyo, 108-8639, Japan.

Abstract

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 factor-alpha 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-κB (NF-κB) 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-κB 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-κB 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-κB 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.

Keywords: Andrographolide; NF-κB; OA treatment; Synovial inflammation; TNFR2 trafficking.