OA is no longer regarded a typical degenerative disease but a multifactorial disease in which chronic inflammation plays a central role . Current treatments for OA can only relieve pain, and no drugs have been approved by the FDA to prevent or slow the progression of the disease. Therefore, we urgently need to develop new drugs that selectively target inflamed joints to prevent damage to healthy tissues. Recent studies have found that vaspin improves the inflammation of chondrocytes by inhibiting the NF-κB pathway . Our present research showed that vaspin reduces osteoarthritis in rats by inhibiting TXNIP/NLRP3 signalling and LPS-mediated activation of NLRP3 inflammasome in chondrocytes. Therefore, we discovered a new mechanism by which vaspin can prevent OA, which further proves the protective effect of vaspin against OA.
The chondrocytes in OA cannot maintain the balance between anabolic and catabolic activities in the tissue, which leads to disturbances in the synthesis and degradation of the extracellular matrix . Various molecular components and mechanisms may turn joint trauma, chronic injury, or overuse into an inflammatory process [15, 16]. The pathogenesis of OA involves several cytokines such as TNF, IL1β, IL15, and leukemia inhibitory factor. Among them, IL1β and TNF are involved in inducing cartilage catabolism and inhibiting anabolic processes that are essential for cartilage homeostasis [17, 18]. Due to the postulated role of IL-1β in the pathology of OA and the main role of inflammasomes in the maturation of IL-1β, the NLRP3 inflammasome has recently received extensive attention. Curcumin or estradiol inhibits the NLRP3 inflammasome and may downregulate inflammatory cytokines and prevent OA progression . The ways to activate NLRP3 have been extensively explored, such as K + efflux and ROS production . Thioredoxin-interacting protein (TXNIP) inhibits cell apoptosis and inflammation by inhibiting thioredoxin (TRX), thereby promoting cell growth and reducing inflammation caused by oxidative stress [21–23]. The results of a study by Seong et al. showed that the ROS-TXNIP-NLRP3 inflammasome axis is crucial in the pathogenesis of inflammation . In the present study, activation of the NLRP3 inflammasome was found in both OA models and LPS-induced chondrocytes, and the activation mechanism may be related to ROS/TXNIP. Activated NLRP3 is responsible for the pathogenic effects of OA, driving cartilage degeneration, and synovitis through the production of IL-1β, IL-18, and matrix-degrading enzymes . They can change the differentiation and function of chondrocytes and stimulate chondrocytes to release cartilage-degrading enzymes, such as metalloproteases (MMPs) and aggrecanases. These enzymes degrade type II collagen and aggrecan from the extracellular matrix, resulting in cartilage loss . Therefore, regulating the NLRP3 inflammasome is crucial to maintaining adequate immune protection while preventing tissue damage caused by the overproduction of cytokines.
Many studies have proposed a link between vaspin and cardiovascular disease . Moreover, vaspin expression in arthritis and its valuable role have been discovered in recent studies [28, 29]. Bao et al. found that the serum vaspin level in OA was higher than that in healthy individuals, and all joint tissues of OA patients, including the cartilage, synovium, meniscus, fat pad, and osteophytes, expressed the vaspin gene . Our study also found that the expression level of vaspin in the serum of OA rats was significantly lower than that in the control group. Although at a low level, vaspin was expressed in the joint tissues, and the expression level in the joint tissues was higher for the OA group than for the control group. Recent studies indicate that Vaspin inhibits the expression of MMP-2 and MMP-9 induced by leptin and that it inhibits the production of NO and TNF-α induced by leptin, indicating that vaspin has anti-inflammatory and anticatabolic effects on chondrocytes . Li et al. found that vaspin prevents diabetic cardiomyopathy (DCM) by inhibiting NLRP3 inflammasome activation . Based on these results, we hypothesized that vaspin would improve the inflammatory response of OA models by inhibiting the activation of the NLRP3 inflammasome. As expected, vaspin inhibited the activation of TXNIP/NLRP3 and the release of inflammatory factors such as IL-1β both in vitro and in vivo. In addition, the knockdown of NLRP3 mimicked the negative regulatory effect of vaspin on the inhibition of NLRP3 inflammasome activation and IL-1β and TNF-α secretion. In vitro experiments showed that vaspin and NAC (ROS inhibitors) significantly reduced ROS production and inhibited NLRP3 inflammasome activation.