Osteoarthritis (OA) is a chronic and progressive degenerative debilitating joint disorder that is characterized by varying degrees of structural defects of articular cartilage, synovial hypertrophy and inflammation, subchondral bone remodeling, laxity of the tendons and ligaments, and the formation of osteophyte [1]. OA is the most common form of arthritis and has a morbidity rate that is as high as 40 % in the elderly population over 70 years old. It frequently leads to joint pain and swelling, mobility limitations, loss of function, and disability [[2], [3], [4]]. As life expectancy and the aging level of the global population have increased, the incidence has continued to increase annually. In clinical terms, the knee, hand, and hip joints are the sites most susceptible to the occurrence of OA. Although obesity, joint trauma, and genetics have been proposed as independent risk factors for OA, age is the most prevalent and prominent [5]. Chondrocytes and ECM are the only two crucial elements of articular cartilage. Chondrocyte is the only resident cell type in cartilage, which is responsible for the biochemical anabolism and catabolism of ECM [6]. ECM degradation is widely regarded as the hallmark and basic feature of OA. It has long been recognized that cartilage is a tissue that is difficult to repair when it is damaged. Chondrocyte chronic damage occurs as age advances under constant biomechanical and biochemical stress, resulting in the excessive secretion of inflammatory markers such as iNOS, COX-2, IL-1β, and TNF-α. These pro-inflammatory cytokines initiate the modification of the inflammatory and immune microenvironments of the articular cavity, negatively impacting ECM homeostasis [7]. This is why osteoarthritis is generally traditionally defined as an aseptic inflammatory disease, and inflammation here refers to a chronic, sterile, low-grade inflammatory state that is driven by endogenous signals in the absence of infections. OA could contribute to the formation of cartilage catabolic substances such as matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin-like motifs (ADAMTS). ECM is chiefly composed of components collagen type Ⅱ and proteoglycans where MMPs (mainly MMP13) are involved in the catabolism of collagen type Ⅱ, while aggrecan (ACAN) is degraded by ADAMTS and MMPs [8,9]. The inhibition of chondrocyte-controlled ECM degradation is a central strategy that is used to slow OA progression. In addition, pro-inflammatory cytokines that are released by synovial tissue undermine articular cartilage by inducing ECM disequilibrium, which can be traced from the clue that synovitis with a high level of macrophages is evident in the late stage of OA [10]. There are currently no available effective curative therapeutic strategies for OA. In the early stage, conservative pharmacological treatments such as topical or oral non-steroidal anti-inflammatory drugs (NSAIDs), steroids, local viscosupplementation, and physiotherapy were only focused on the management of symptoms such as the relief of stiffness and arthralgia. Arthroplasty is the gold standard and final option for end-stage OA patients who have severe symptoms. Therefore, a thorough insight and elucidation into the mechanism of OA occurrence and progression are crucial for the development of disease-modifying agents.

Senescence is a physiological process of age-dependent functional decline of organisms that has a close correlation with gradual organ and tissue deterioration, the progressive loss of somatic function, and increased risk for pathologies of age-related chronic diseases such as initiation and progression. Cellular senescence is a permanent cell-cycle arrest state or the inability of cells to proliferate and is a stress response for eliminating damaged cells driven by multiple endogenous and exogenous stress stimuli such as ROS, telomere dysfunction, DNA damage, and inflammatory cytokines [11,12]. Cellular senescence is believed to be the hallmark of aging and the senescent cells (SC) secrete a host of pro-inflammatory factors (IL-1α, IL-1β, IL-6, IL-8, TNF-α), growth factors (TGF-β, PDGF-AA, and IGFBPs), chemokines (CCL-2, CCL-20, CCL-7, CXCL-4, CXCL1, and CXCL-12), and matrix-degrading molecules (MMP3, MMP9), which are collectively termed as the senescence-associated secretory phenotype (SASP). This is implicated in SC-linked pathogenesis and regulatory effects in tissue regeneration and repair of age-related diseases such as OA [[13], [14], [15], [16]]. As a consequence, targeting SC accumulation with exhibiting SASP is regarded as a potential therapeutic strategy for multiple age-related pathologies of chronic sterile inflammation in the selective clearance of SC or SASP blockage. The fact that the pharmacological removal of SC has been found to extend the health span and lifespan of naturally aged mice is the most compelling evidence for the causal role of cellular senescence in aging [17]. Multiple studies have also suggested other molecular mechanism hallmarks of aging: DNA instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, stem cell exhaustion, and altered intercellular communication [18]. Traditional SASP is strikingly similar to the characteristic secretion of articular cartilage inflammation (IL-1β, IL-6, TNF-α) and ECM catabolic molecules (mainly MMP13) that are present in OA pathogenesis. It has been reported that OA chondrocytes exhibit ascending levels of senescent markers: senescence-associated beta-galactosidase (SA-β-gal) activity, telomere attrition, and upregulation of cellular senescence biomarkers P16 and P21. This shows that SC within articular cartilage plays a pathological role in OA causation [15]. In addition to spontaneous aging-induced OA, chondrocyte senescence can arise from trauma due to a chronically sustained stress state, and intra-articular delivery of senolytics rapamycin can serve to induce autophagy, prevent senescence, and delay the progression of age-associated and post-traumatic OA [19]. A recent study found SC transplant into normal knee joints to induce indicative OA pathological features that are manifested by severe articular cartilage damage in the regions of the lateral and medial tibial plateaus and the femoral condyles, further strengthening the evidence that SC is a direct participant in the OA pathological process [20].

Sirtuin 6 (SIRT6) is a member of the sirtuin family of evolutionarily highly conservative NAD+-dependent histone deacetylases and is a chromatin regulatory protein that plays crucial roles in genome transcription. The sirtuin family is comprised of seven enzymes (SIRT1-7) that share conserved core catalytic domains, but differ in terms of specific tissue distribution, cellular localization, unique substrates, and multiple physiological and pathological functions [21,22]. SIRT6 has been recognized to be exclusively localized in the nucleus and possesses enzymatic activities of deacetylation and ribosylation [[23], [24], [25]]. SIRT6-dependent nuclear histone deacetylation that targets H3K56ac and H3K9ac has been implicated in integrating glucose/lipid metabolism, DNA stability, inflammation, oxidative stress, aging, and senescence-related diseases [26,27]. As the loss of SIRT6 in mice led to them exhibiting genomic instability, premature aging, and shortened lifetime, SIRT6 has long been believed to be a longevity protein [28,29]. Notably, during OA, chondrocytes ablated for SIRT6 aggravated osteoarthritis by controlling DNA repair and telomere dysfunction, while pharmacological overexpression of SIRT6 was found to suppress cellular senescence and NF-κB mediated inflammatory responses to delay OA development [30,31]. In addition, intra-articular administration of adenovirus-SIRT6 can relieve surgery-induced OA pathological manifestations through interaction with STAT5 [32]. SIRT6 may provide a potentially curative approach for OA, although the specific mechanisms of downstream elements or signaling pathways still remain relatively obscure.

FST (3,7,3′,4′-tetrahydroxyflavone) is a natural bioactive flavonoid that is derived from plant extracts such as cucumber, onion, apple, and strawberry with the highest reported contents in strawberries [33]. It has been shown to bear multiple pharmacological benefits, including anti-inflammatory [34], anti-apoptotic [35], antioxidant [36], anti-tumorigenic [37], anti-angiogenic [38,39], and anti-senescent effects [40]. An in vitro study certified the flavonoid polyphenol FST as having greater senotherapeutic activity than quercetin in cultured cells [41]. In addition, FST was found to suppress the activity of some pro-inflammatory cytokines of TNF-α, IL-6, and the transcription factor NF-κB, while facilitating the synthesis of glutathione, which is an endogenous antioxidant [[42], [43], [44]]. However, only one previous in vivo animal study has examined the effect of FST on OA not targeting aging [45]. Due to these previous findings, it can reasonably be assumed that FST may exert a chondroprotective role by targeting the elimination of senescent chondrocytes, but limited mechanisms are currently understood.

This study identified the affinity of FST with SIRT6 through molecular docking. In addition, the ability of FST to postpone cartilage degradation, blunt inflammation, and attenuate chondrocyte senescence in the OA rat model was investigated. The effects of FST on senescent cells and SASP in the OA knee joints of an experimental rat model and in cultured chondrocytes were also examined.