Vanillic Acid Reduces Pain-Related Behavior in Knee Osteoarthritis Rats Through the Inhibition of NLRP3 Inflammasome-Related Synovitis

Zhenyuan Ma,Peimin Wang,Bo Xu,Taiyang Liao,Zhengquan Huang,Haosheng Zhang,Xiaoqing Shi,Xiaochen Li,Yancheng Xiao,Li Zhang

doi:10.3389/fphar.2020.599022

Zhenyuan Ma, Peimin Wang + Show 8 more

Open Access

https://doi.org/10.3389/fphar.2020.599022

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Abstract

Objectives: Synovitis plays an important role in knee osteoarthritis (KOA) pain. The activation of the NOD-like receptor protein 3 (NLRP3) inflammasome in fibroblast-like synoviocytes (FLSs) promotes KOA development. In this study, we aimed to investigate whether vanillic acid (VA), a monomer derived from Chinese herbal medicines, could target NLRP3 inflammasome-related synovitis to reduce pain. Methods: Rats in the KOA and KOA + VA groups were injected with monosodium iodoacetate (MIA) in the knee to induce KOA. From day 14, the KOA + VA group was given VA at 30 mg/kg every day via gastric intubation. FLSs were collected from the synovial tissues. We examined both the protein and gene expression of caspase-1, apoptosis-associated speck-like protein with a caspase recruitment domain (ASC), NLRP3, components of the NLRP3 inflammasome, and interleukin-1β (IL-1β) and IL-18 in vivo and in vitro. Results: The upregulation of caspase-1, ASC, and NLRP3 in the KOA model were reduced by VA. VA also lowered the level of IL-1β and IL-18 in the KOA model. In addition, VA relieved pain-related behavior of KOA model rats and downregulated the pain mediators CGRP, NGF, and TrkA in FLSs. Interestingly, we also observed reduced synovial fibrosis in the animal experiments. Conclusion: Our research showed that VA reduces synovitis and pain-related behaviors in a rat model of KOA, which provides the basis for further investigations into the potential therapeutic impact of VA in KOA.

Highlights

Knee osteoarthritis (KOA) is one of the most common chronic degenerative bone diseases and joint pain is the main clinical symptom that needs to be solved urgently (Litwic et al, 2013)
To explore whether vanillic acid (VA) inhibits NOD-like receptor protein 3 (NLRP3) activation in vivo, we analyzed the expression of caspase-1, NLRP3, and a caspase recruitment domain (ASC) in the Normal group, KOA group, and KOA + VA group
The mRNA and protein expressions of caspase-1, NLRP3, and ASC (Figures 1A–C) in the KOA group were higher than those in the normal group (p < 0.05), whereas the KOA + VA group showed a reduction compared to the KOA group (p < 0.05)

Summary

Introduction

Knee osteoarthritis (KOA) is one of the most common chronic degenerative bone diseases and joint pain is the main clinical symptom that needs to be solved urgently (Litwic et al, 2013). The occurrence and development of KOA are associated with all the tissues that make up the knee joint, such as the synovium, cartilage, subchondral bone, and subcondylar fat pads (Muratovic et al, 2019). As an immune-related disease, the inflammation of the synovium in KOA plays a vital role and leads directly to the related pain (Atukorala et al, 2013). Recent studies have revealed that the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome is the beginning of inflammatory cascade amplification and is strongly correlated to hepatitis, pneumonia, nephritis, and other types of chronic aseptic inflammation (Ferrucci and Fabbri, 2018). Our previous study showed that activation in KOA fibroblast-like synoviocytes (FLSs) promoted the development of synovitis (Zhao et al, 2018; Zhang et al, 2019)

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