Chrysin ameliorates synovitis and fibrosis of osteoarthritic fibroblast-like synoviocytes in rats through PERK/TXNIP/NLRP3 signaling

Abstract

Objective: Synovitis and fibrosis are common pathological features of knee osteoarthritis (KOA). The interaction of synovitis and fibrosis can promote KOA progression. Chrysin (CHR), a natural flavonoid, may treat inflammation and prevent fibrosis. However, the effect and mechanism of CHR in KOA synovitis and fibrosis remains unclear.Methods: The KOA model was established in male SD rats by anterior cruciate ligament transection (ACLT), and histological analysis was used to evaluate synovitis and fibrosis. IL-6, IL-1β and TNF-α mRNA expression in synovial tissue was measured by qRT‒PCR. Immunohistochemistry (IHC) was performed to detect GRP78, ATF-6 and TXNIP expression in vivo. Synovial fibroblasts (SFs) were treated with TGF-β1 to stimulate the inflammatory response and fibrosis. CCK-8 assays were used to detect the viability of CHR-treated SFs. The IL-1β level was detected by immunofluorescence analysis. Coimmunoprecipitation (Co-IP) and double immunofluorescence colocalization were used to detect the physiological interaction between TXNIP and NLRP3. The expression of fibrosis-related mediators and PERK/TXNIP/NLRP3 signaling molecules was detected by western blotting and qRT-PCR.Results: Four weeks after CHR treatment, pathological sections and associated scores showed that CHR improved synovitis and fibrosis in the ACLT model. In vitro, CHR attenuated the TGF-β1-induced inflammatory response and fibrosis in SFs. Moreover, CHR suppressed the expression of synovial fibrosis markers and PERK/TXNIP/NLRP3 signaling molecules in the synovial tissue of rats with ACLT and cultured SFs. More importantly, we found that CHR inhibited TXNIP-NLRP3 interactions in TGF-β-induced SFs.Conclusion: Our findings indicate that CHR can ameliorate synovitis and fibrosis in KOA. The underlying mechanism may be related to the PERK/TXNIP/NLRP3 signaling pathway.

Chrysin-based supramolecular cyclodextrin-calixarene drug delivery system: a novel approach for attenuating cardiac fibrosis in chronic diabetes

“…This 5,7-dihydroxyflavone was characterized by antioxidant, antitumor, anti-hypercholesterolemic and anti-inflammatory activities ( Bae et al, 2011 ; Brechbuhl et al, 2012 ; Ali et al, 2014b ; Anandhi et al, 2014 ; Samarghandian et al, 2016 ; Phan et al, 2021 ). Our data are in line with other research that identified CHR-mediated inhibition of pro-fibrotic pathways in rat myocardial injury, renal fibrosis and osteoarthritis, by reducing TGF-β1/Smad3, p38, Erk1/2, MMP2 and PERK/TXNIP/NLRP3 signalling ( Rani et al, 2015 ; Nagavally et al, 2021 ; Ding et al, 2023 ). Additionally, by using a different pharmacological approach, we demonstrated that TGF-β/Smad pathway can be reduced in human retinal pigment epithelial cells exposed to high glucose by using calixarene OTX008, a selective inhibitor Gal-1 ( Trotta et al, 2022 ).…”

Advancements and recent explorations of anti-cancer activity of chrysin: from molecular targets to therapeutic perspective

“…Inflammation is prevented by CH treatment because it decreased lipid metabolism by inhibiting AMPK and inflammasome activation by blocking NLRP3 [ 50 ]. CH may treat inflammation and prevent fibrosis by decreasing the inflammatory response and fibrosis induced by TGF-β1 in synovial fibroblasts (SFs) via inhibiting thioredoxin-interacting protein (TXNIP)-NLRP3 interactions in TGF-β-induced SFs [ 51 ]. CH reduces hypercholesterolemia-mediated atherosclerosis via modulating the inflammatory genes expression including TNF-α , toll-like receptors ( TLR4 ), IL-17 , and NLRP3 in the intestine and aorta compared with hypercholesterolemia control rats [ 52 ].…”

Osteoarthritis in the Elderly Population: Preclinical Evidence of Nutrigenomic Activities of Flavonoids

“…Flavones are obtained by dehydrogenation of flavanones, and they are the most representative class of flavonoids. We have found fifteen manuscripts on 11 molecules: acacetin, apigenin, chrysin, diosmetin (DIOS; 3′,5,7-trihydroxy-4′-methoxy flavone), luteolin, nepetin, orientin, oroxylin-A, rhoifolin (ROF), scutellarin, and velutin [ 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ]. Acacetin (5,7-dihydroxy-4′-methoxyflavone) is the major bioactive component of the traditional Chinese medicine “Snow lotus” ( Saussurea involucrata ) and is present in some plants, such as Robinia pseudoacacia , Turnera diffusa, and Betula pendula .…”

“…Chrysin also exhibits some in vivo biological activities, as demonstrated in a rat knee MIA-induced OA model. By experiments of quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence, the authors demonstrated that chrysin decreased inflammation status, reduced some other OA endpoints, inhibited NLRP-3 inflammasome activation, and ultimately alleviated the synovitis [ 55 ]. More recently, some authors, through in vivo and in vitro studies, while confirming these data, have added the important detail that chrysin also reduced the inflammatory response induced by TGF-β1 and fibrosis in FLSs with the conclusion that it can improve synovitis and fibrosis in knee OA by performing, among others, this specific mechanism of action [ 56 ].…”