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Oleanolic Acid Decreases IL-1?-Induced Activation of Fibroblast-Like Synoviocytes via the SIRT3-NF-?B Axis in Osteoarthritis.

ABSTRACT: Synovial inflammation is a major pathological feature of osteoarthritis (OA), which is a chronic degenerative joint disease. Fibroblast-like synoviocytes (FLS), localized in the synovial membrane, are specialized secretory cells. During OA synovitis, FLS produce chemokines and cytokines that stimulate chondrocytes to secrete inflammatory cytokines and activate matrix metalloproteinases (MMPs) in FLS. Recent studies have demonstrated that sirtuin 3 (SIRT3) performs as a key regulator in maintaining mitochondrial homeostasis in OA. This study aims at ascertaining whether SIRT3 is involved in OA synovitis. The overexpression (OE) and knockdown (KD) of SIRT3 are established by short hairpin RNA (shRNA) and recombinant plasmid in human FLS. The anti-inflammatory effect of SIRT3 underlying in oleanolic acid- (OLA-) prevented interleukin-1?- (IL-1?-) induced FLS dysfunction is then evaluated in vitro. Additionally, the molecular mechanisms of SIRT3 are assessed, and the interaction between SIRT3 and NF-?B is investigated. The data suggested that SIRT3 can be detected in human synovial tissues during OA, and OLA could elevate SIRT3 expression. OE-SIRT3 and OLA exhibited equal authenticity to repress inflammation and reverse oxidative stress changes in IL-1?-induced human FLS dysfunction. KD-SIRT3 was found to exacerbate inflammation and oxidative stress changes in human FLS. Furthermore, it was found that SIRT3 could directly bind with NF-?B, resulting in the suppression of NF-?B activation induced by IL-1? in human FLS, which then repressed synovial inflammation in OA. In general, the activation of SIRT3 by OLA inhibited synovial inflammation by suppressing the NF-?B signal pathway in FLS, and this suggested that SIRT3 is a potential target for OA synovitis therapy.

SUBMITTER: Bao J

PROVIDER: S-EPMC7542488 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Oleanolic Acid Decreases IL-1<i>β</i>-Induced Activation of Fibroblast-Like Synoviocytes via the SIRT3-NF-<i>κ</i>B Axis in Osteoarthritis.

Bao Jiapeng J Yan Weifeng W Xu Kai K Chen Mengyao M Chen Zhonggai Z Ran Jisheng J Xiong Yan Y Wu Lidong L Wu Lidong L

Oxidative medicine and cellular longevity 20200928

Synovial inflammation is a major pathological feature of osteoarthritis (OA), which is a chronic degenerative joint disease. Fibroblast-like synoviocytes (FLS), localized in the synovial membrane, are specialized secretory cells. During OA synovitis, FLS produce chemokines and cytokines that stimulate chondrocytes to secrete inflammatory cytokines and activate matrix metalloproteinases (MMPs) in FLS. Recent studies have demonstrated that sirtuin 3 (SIRT3) performs as a key regulator in maintaini ...[more]

PMID: 33062145

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Project description:High mobility group box 1 (HMGB1) is an important downstream product of pyroptosis in macrophages, and it serves a vital role in numerous inflammatory diseases. Previous studies have reported that HMGB1 is released by fibroblast?like synoviocytes (FLSs) that are activated by inflammatory cytokines in knee osteoarthritis (KOA); however, the mechanism via which FLS promotes HMGB1 secretion in KOA remains unknown. According to our previous study, pyroptosis occurs in FLSs of patients with KOA and is mediated by Nod?like receptor protein (NLRP)1 or NLRP3 inflammasomes. However, the specific relationship between HMGB1 secretion and FLS pyroptosis requires further investigation. In the present study, the association between HMGB1 secretion and FLS pyroptosis was investigated in vitro and in vivo. In this study, western blotting, ELISA and reverse transcription?quantitative PCR were used to measure expression levels of proteins and mRNA. Caspase?1 activity assay and Hoechst 33342/PI double staining were used to observe the pyroptosis of FLSs. Hematoxylin and eosin staining was used to observe the destruction of cartilage in KOA. Increased expression levels of pyroptosis?related proteins and HMGB1 in the synovium of rat anterior cruciate ligament transection?induced KOA models were identified, and these changes were significantly mitigated via the intra?articular injection of a caspase?1 inhibitor. In vitro, FLSs were treated with lipopolysaccharide (LPS) + ATP to induce pyroptosis, and HMGB1 secretion was subsequently measured. LPS + ATP significantly increased the expression levels of pyroptosis?related proteins and HMGB1 in FLSs, and these effects were significantly mitigated by small interfering RNAs targeting NLRP1, NLRP3, apoptosis?associated speck?like protein with a caspase?recruitment domain or caspase?1. Therefore, the present results indicated that NLRP1/NLRP3 inflammasome?mediated and caspase?1?dependent FLS pyroptosis increased HMGB1 secretion in KOA. These findings may provide a therapeutic strategy to decrease synovial inflammatory responses during KOA progression.

Dataset Information

Oleanolic Acid Decreases IL-1?-Induced Activation of Fibroblast-Like Synoviocytes via the SIRT3-NF-?B Axis in Osteoarthritis.

Publications

Oleanolic Acid Decreases IL-1<i>β</i>-Induced Activation of Fibroblast-Like Synoviocytes via the SIRT3-NF-<i>κ</i>B Axis in Osteoarthritis.

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