Cholesterol metabolism is involved in the pathogenesis of osteoarthritis (OA), and a high cholesterol level has been identified as a possible risk factor for OA (Farnaghi et al., 2017). Statins, the inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, have been reported to exert chondroprotective effects, as evidenced by their ability to inhibit the synthesis of cartilaginous extracellular matrix-degrading enzymes to ameliorate cellular senescence, and to accelerate proteoglycan production in articular chondrocytes (Yudoh and Karasawa, 2010). Both lipophilic (simvastatin) and hydrophilic (pravastatin) statins can reduce proinflammatory mediator levels in lipopolysaccharide-stimulated porcine articular chondrocytes (Chang et al., 2014). Similarly, pravastatin restored the interleukin-1 beta (IL-1β)-impaired autophagic flux and reduced inflammatory responses of rat articular chondrocytes (Mao et al., 2018). In an IL-1β-stimulated SW1353 chondrosarcoma cell line, simvastatin downregulated the expression of the catabolic genes matrix metalloproteinase-2 (MMP-2), MMP-3, MMP-9, MMP-13, and tissue inhibitor of metalloproteinase-2 (TIMP-2) in a dose-dependent manner (Cecen et al., 2019). A study demonstrated that simvastatin inhibited IL-1β + oncostatin M-induced CD44 fragmentation and increased pericellular matrix retention in human and bovine chondrocytes (Terabe et al., 2016). Similarly, in human OA chondrocytes, atorvastatin reduced the MMP-13 mRNA expression and protein production while upregulating the mRNA level of aggrecan and type II collagen (Simopoulou et al., 2010).

Despite the potential of statins for treating inflammatory arthritis, the effects of statins on the synovium have not yet been fully demonstrated. Early-onset OA is directly linked to synovitis, and pathological changes in the synovium occur earlier than the degeneration of the cartilaginous matrix (Mathiessen and Conaghan, 2017). Through the inhibition of synovial inflammation, mevastatin could reduce cartilage degradation in a rabbit OA model (Akasaki et al., 2009). An animal study demonstrated that the intraarticular injection of lovastatin ameliorated articular cartilage degeneration through the downregulation of MMP-1 and MMP-3 in the synovium but not in the cartilage of rabbits that underwent anterior cruciate ligament transection (Fan and Yang, 2009). In addition, the impairment of hyaluronan (HA) secretion and molecular weight distribution were also detected in inflamed fibroblast-like synoviocytes (FLSs) (Tang et al., 2018; Band et al., 2015). However, high doses of simvastatin have been reported to induce apoptosis in activated FLSs (Litinsky et al., 2009). To expand on the aforementioned findings, the present study examined the effects of statins on human FLSs.