Oleanolic Acid Decreases IL-1β-Induced Activation of Fibroblast-Like Synoviocytes via the SIRT3-NF-κB 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-1β- (IL-1β-) induced FLS dysfunction is then evaluated in vitro. Additionally, the molecular mechanisms of SIRT3 are assessed, and the interaction between SIRT3 and NF-κB 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-1β-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-κB, resulting in the suppression of NF-κB activation induced by IL-1β 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-κB signal pathway in FLS, and this suggested that SIRT3 is a potential target for OA synovitis therapy.

Nrf2 Regulates CHI3L1 to Suppress Inflammation and Improve Post-Traumatic Osteoarthritis

“…1,2,23 The synovium plays a key role in maintaining joint homeostasis, lubricating the joint and facilitating the flow of synovial fluid therein. 26 Herein, we observed clear signs of synovial fibrosis in ACLT model mice, consistent with the impairment of synovial function. Coleman et al 27 determined that intra-articular N-acetylcysteine (NAC) injection can effectively prevent PTOA via suppressing oxidative stress in model experimental systems.…”

Pirfenidone attenuates synovial fibrosis and postpones the progression of osteoarthritis by anti-fibrotic and anti-inflammatory properties in vivo and in vitro

“…FLSs were isolated by enzymatic digestion of the synovial tissue obtained from patients with OA undergoing total knee arthroplasty (TKA), as described previously [ 20 ]. Briefly, specimens were minced into small pieces and then digested with 4 mg/ml type I collagenase (Solarbio, Beijing, China) for an hour at 37 °C within an atmosphere containing 5% CO 2 .…”

α‐Lipoic Acid Targeting PDK1/NRF2 Axis Contributes to the Apoptosis Effect of Lung Cancer Cells

“…As LA acts as a cofactor of PDH, the latter switches the glycolysis to OXPHOS. According to the Warburg effect, most cancer cells tend to undergo glycolysis, including A549 and PC9 lung cancer cell lines [ 28 ], so we assume that LA influences the antioxidant system by regulating the mitochondrial metabolic enzymes. As assumed, PDK1 (the PDH kinase, which could phosphorylate PDH and rendering its inactivity), when processed with LA, could be inhibited in both the cell lines in a dose-dependent manner ( Figure 4(a) ).…”

“…Nevertheless, the clinical effect and application still need to be evaluated. The NSCLC cell lines A549 and PC9 have been reported to prefer glycolysis for energy supply [ 28 ]. So, we test if LA could influence the metabolic feature and directly regulate the antioxidant system to promote apoptosis on these two cell lines.…”