Abstract

Osteoarthitis (OA) is the most common aging-related joint pathology; the aging process results in changes to joint tissues that ultimately contribute to the development of OA. Articular chondrocytes exhibit an aging-related decline in their proliferative and synthetic capacity. Sirtuin 1 (SIRT 1), a longevity gene related to many diseases associated with aging, is a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase and master metabolic regulator. Along with its natural activator resveratrol, SIRT 1 actively participates in the OA pathological progress. SIRT 1 expression in osteoarthritic cartilage decreases in the disease progression of OA; it appears to play a predominantly regulatory role in OA. SIRT 1 can regulate the expression of extracellular matrix (ECM)-related proteins; promote mesenchymal stem cell differentiation; play anti-catabolic, anti-inflammatory, anti-oxidative stress, and anti-apoptosis roles; participate in the autophagic process; and regulate bone homeostasis in OA. Resveratrol can activate SIRT 1 in order to inhibit OA disease progression. In the future, activating SIRT 1 via resveratrol with improved bioavailability may be an appropriate therapeutic approach for OA.

Introduction

Osteoarthitis (OA), the most common aging-related joint pathology, is characterized by articular cartilage destruction along with changes occurring in other joint components, including bone, menisci, synovium, ligaments, capsule, and muscles [1]. In western populations, OA is one of the most frequent causes of pain, loss of function, and disability in adults [2]. The etiology of OA is mostly unclear, but several factors are suggested to be involved in the pathogenesis of OA, including mechanical, genetic, and aging-associated factors that ultimately lead to synovitis, apoptosis, and cartilage destruction. Advanced age is the greatest risk factor for OA [3]. Radiographic evidence of OA occurs in the majority of people by 65 years of age and in about 80% of those aged over 75 years [2]. The aging-related changes in joint tissues that contribute to the development of OA include cell senescence and aging changes in the extracellular matrix [4]. The sirtuins (SIRTs) family is a well-known group of antiaging genes [5]. It has been recently confirmed that the Silent information regulator 2 type 1 (also known as sirtuin 1 [SIRT 1]) is linked to various age-associated diseases such as obesity, type 2 diabetes, cardiovascular disease, cancer, dementia, arthritis, osteoporosis, as well as with OA [6]. It is essential to elucidate the roles of SIRT 1 and its natural activator, resveratrol, in the pathogenesis of OA in order to develop new successful approaches to the treatment of OA.

Structure and basic function of SIRT 1

Nicotinamide adenine dinucleotide (NAD+) is a classical coenzyme mediating many redox reactions and an essential compound for many enzymatic processes [7]. In redox reactions, cellular levels of NAD+ are an important indicator of the cellular energy status; NAD+ can readily switch from the electron accepting form (oxidizing) NAD+ to the electron-donating form (reducing) NADH and vice versa [8]. SIRT 1 is an NAD+-dependent protein deacetylase and is a master metabolic regulator in different metabolic tissues [9].

The SIRTs are members of the silent information regulator 2 (SIR 2) family of highly conserved NAD+-dependent histone/protein deacetylases; they are a pivotal regulator of longevity and health span [10]. The SIRTs are associated with numerous cellular signaling pathways that include anti-inflammation, senescence, apoptosis, DNA damage repair, autophagy, and regulation metabolism in response to the cellular energy and redox status [11]. There are seven mammalian sirtuins, SIRT 1–7. SIRT 1 and SIRT 2 are localized in the nucleus and cytoplasm; SIRT 3, SIRT 4, and SIRT 5 are mitochondrial; and SIRT 6 and SIRT 7 are nuclear [12]. Each sirtuin contains a highly conserved catalytic core domain of approximately 275 amino acids which functions as a NAD+-dependent deacetylase and/or ADP-ribosyltransferase [13]. SIRT 1, the most-conserved mammalian NAD+-dependent protein deacetylase shares closest homology to yeast SIR 2. SIRT 1 splits NAD+ into nicotinamide and ADP-ribose, then transfers the acetyl group from the protein substrate to the 20-OH group of the ribose ring in the ADP-ribose molecule [9]. Histone deacetylases, in particular the sirtuin family with SIRT 1 as the major player, have long been linked to aging [14]. SIRT 1 is related to multiple age-associated diseases on account of its capacity to deacetylate histones and non-histone proteins such as tumor protein p53 (p53), kB-gene binding nuclear factor (NF-κB), heat shock factor 1 (HSF1), forkhead box transcription factor, class O (FOXOs), and peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1 (PGC-1); thus, it’s able to regulate the cell’s biology, metabolism, and fate at different levels [15]. In mammalian cells, nutrient availability regulates the lifespan; p53, FOXO3a, and SIRT 1 – three proteins separately implicated in aging – constitute a nutrient-sensing pathway [16].

Resveratrol is a polyphenol found in the skin of red grapes and various other fruits, wines, peanuts, and root extracts of the weed Polygonum cuspidatum. It is thought to harbor major health benefits and is reported to be a substrate-specific activator of yeast SIR 2 and human SIRT 1 in vivo and in vitro [17]. Resveratrol is the most potent natural compound that activates SIRT 1, mimicking the positive effects of calorie restriction. In yeast, resveratrol mimics calorie restriction and increases DNA stability and extending lifespan by 70% [18]. In addition, resveratrol has shown to increase the lifespan of three model organisms through a SIR 2-dependent pathway [17,19]. Resveratrol increases cell survival by stimulating SIRT 1-dependent deacetylation of p53 [18]. Currently, aims to develop resveratrol with better bioavailability and targeting SIRT 1 at lower concentrations have shown promise [18].

Expression of SIRT 1 in OA

The articular cartilage is an avascular, aneural, alymphatic, and viscoelastic connective tissue that derives its nutrition and oxygen supply by diffusion from the synovial fluid; along with subchondral bone, the articular cartilage is maintained at a low oxygen environment throughout life [20,21]. Chondrocytes are the only resident cells found in cartilage and are responsible for both the synthesis and turnover of the abundant extracellular matrix (ECM). Articular chondrocytes exhibit an age-related decline in their proliferative and synthetic capacity while maintaining the ability to produce pro-inflammatory mediators and matrices-degrading enzymes [22]. These findings are characteristic of the senescent secretory phenotype and are most likely a consequence of extrinsic stress-induced senescence driven by oxidative stress, rather than intrinsic replicative senescence. ECM changes, including the accumulation of proteins modified by non-enzymatic glycation, contribute to the propensity of developing OA [22,23].

Expression of the SIRT 1 protein is present in the nuclei of chondrocytes in all layers of the cartilage tissue as well as in synovial tissues [24,25]. All catabolic, mechanical, and nutritional stresses inhibit SIRT 1 expression [24]. Tumor necrosis factor-α (TNF-α), the main proinflammatory factor, could induce SIRT1 cleavage and reduce SIRT1 activity [26]. Oxidative stress-induced reduction of SIRT1 through post-translational modifications decrease SIRT1 activity and mark the protein for proteasomal degradation [27]. Accordingly, treatment with H2O2 results in the down-regulation of SIRT1 protein expression [28]. On the other hand, activation of the SIRT1 and related signaling pathway attenuates mitochondrial dysfunction and biogenesis [29], and defends against oxidative stress in articular chondrocytes [28].

It has been confirmed that SIRT 1 protein expression decreases in severely degenerated human cartilage, leading chondrocytes to hypertrophy and degeneration [30]. In patients with knee OA, expression levels of SIRT 1 are decreased in the articular cartilage (the lateral and medial sides of the tibia plateau including the loading zone and the margin zone) and is negatively associated with OA disease severity [30,31]. Moreover, SIRT 1’s downstream gene p53 expression and its acetylation level were dramatically increased in knee OA cartilage and is positively related to OA severity [31]. However, SIRT 1 expression was significantly reduced in human osteoarthritic subchondral osteoblasts compared with normal [32]. In contrast, SIRT 1 activity (cytoplasmic and nuclear) from peripheral blood mononuclear cells did not correlate with OA patients’ clinical activity (Lequesne’s index) or inflammation (erythrocyte sedimentation rate, C-reactive protein); in fact, it did not differ between patients with OA and healthy controls but instead correlates with the baseline interleukin (IL) -6 [33]. In wild-type mice with experimental knee OA, SIRT 1-positive chondrocytes are distributed from the superficial to the deep zone of the cartilage. Here, levels of SIRT 1 protein first increased but then gradually decreased with aging [34]. Synovial fluid from OA patients may contain proinflammatory cytokines including TNF-α, which could generate a stable and enzymatically inactive 75-kd form of SIRT 1. When human chondrocytes were exposed to OA-derived synovial fluid, the 75-kd SIRT 1 fragment was indeed generated, and levels of 75-kd SIRT 1 was elevated in OA versus normal chondrocytes [35].

Effect of SIRT 1 in OA

SIRT 1 regulates ECM

SIRT 1 seemsmicroM to play a predominant regulatory role in OA [36]. Expression of SIRT 1 in chondrocytes led to increased chondrocyte survival in either the presence or absence of TNF-α/actinomycin D [37]. Elevation of SIRT 1 protein levels or activity in human OA chondrocytes led to a dramatic increase in cartilage-specific gene (collagen II and aggrecan) expression; accordingly, 3D human chondrocytes present with both increased cellular SIRT1 enzymatic activity and COL2A1 expression [38,39]. Reduced expression of COL2A1 mRNA and type II collagen protein in human chondrocytes correlates with decreased SIRT 1 activity [39]. Another study confirmed SIRT 1 inhibition increases COL10A1 and ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs) expression while decreasing aggrecan expression [30]. It was discovered recently that glucosamine (GlcN) exhibits chondroprotective action on OA by enhancing the mRNA expression and protein levels of SIRT 1 and its downstream gene COL2A1 in chondrocytes [40].

SIRT 1 promotes MSCs differentiation

SIRT 1 is required for promoting chondrogenic differentiation of mesenchymal stem cells (MSCs) [41]. It’s well known that sex determining region Y box protein 9 (SOX9) and runt-related transcription factor 2 (RUNX2) are the pivotal transcription factors in adult cartilage development [42]. SIRT 1 supports the chondrogenic development of MSCs at least in part through the inhibition/deacetylation of NF-κB and activation of SOX9 in vitro [41]. SIRT 1 may regulate the expression of RUNX2 and the production of matrix metalloproteinase (MMP) 13 from chondrocytes to adjust the hypertrophic chondrocyte lineage and degeneration of articular cartilage [43]. SIRT 1 deacetylates PPARγ and SOX9 to control the vav guanine nucleotide exchange factor 1 (Vav1), regulating MSC cell fate decisions for adipocyte and chondrocyte differentiation [44]. SIRT 1 is a major contributor of SOX9 deacetylation; the deacetylated state of SOX9 enables its importation to the nucleus and supports its transcriptional activity and transactivation of aggrecan [45]. SIRT 1 is active in the cartilage-specific transcription factor SOX9 and is dependent on NAD. Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) leads to reductions in NAD levels, SIRT activity, and cartilage-specific gene expression. Therefore, SIRT 1, NAMPT, and NAD may provide a positive function in human cartilage by elevating the expression of genes encoding cartilage ECM [38]. SIRT 1 is also a key regulator of chondrocytes’ phenotype; IL-1β induces the de-differentiation of articular chondrocytes by the up-regulation of SIRT 1 activity enhanced by both NAMPT and extracellular signal-regulated kinases (ERK) signaling [46]. Decreased SIRT 1 in OA might lead chondrocytes to hypertrophy and degenerate [30]. SIRT1 plays an important role in MSCs’ differentiation and resistance to H2O2-induced oxidative stress during bone marrow-derived MSC (BM-MSC) osteogenesis [47,48]. In the SIRT1 RNAi cell model, knocking down the SIRT1 gene induced the Wnt signaling pathway, leading to the inhibition and decrease of cartilaginous proliferation and differentiation, but increasing apoptosis in ATDC5 cells [49]. Increased SIRT1 could inhibit adipogenesis and stimulate myogenic differentiation in MSCs through activating Wnt/β-catenin signaling [50,51]. Other factors were also involved in the process of SIRT1 regulation of MSC, such as the activation of the adenosine monophosphate-activated protein kinase (AMPK)-SIRT1 signaling pathway as well as beneficial mechanical stretch to induce antioxidant responses, attenuate intracellular reactive oxygen species (ROS), and improve osteogenesis of human BM-MSCs [52]. In mice, Sirt1 promotes MSC proliferation and osteogenic differentiation and inhibits MSC senescence via Bmi1 activation; therefore, treatment with resveratrol could promote bone formation and prevent bone loss [53]. SIRT1 was also directly involved in the regulation of beige adipocyte differentiation. Elevated SIRT1 prevents elderly adipose tissue-derived MSCs from entering senescence and restores the beige differentiation ability via the p53/p21 pathway [54].

Anti-catabolic and anti-inflammatory effects

Previous studies confirmed that SIRT 1 exhibits anti-catabolic and anti-inflammatory effects in OA. Secreted inflammatory molecules, in particular the two major proinflammatory cytokines IL-1β and TNF-α, control the degeneration of articular cartilage matrix [55,56]. SIRT 1 and TNF-α appear to have opposing effects on cartilage gene expression; SIRT 1 expression or activity may be blocked in part by TNF-α [26]. TNF-α mediates the proteolytic cleavage of SIRT 1, producing a stable 75-kd SIRT 1 fragment that is incapable of binding chromatin and chromatin-associated coactivators, such as PGC-1 and SOX9 [26]. After the exposure of human chondrocytes to TNF-α, 75-kd SIRT 1 was exported to the cytoplasm and co-localized with the mitochondrial membrane, where the 75-kd SIRT 1 plays the role of preventing cell death through its enhanced association with cytochrome on the mitochondrial membrane to block downstream apoptosis by preventing apoptosome assembly and subsequent caspase 3 activation; 75-kd SIRT 1 is capable of promoting cell survival through an enzymatically independent mechanism [35]. Cartilage destruction in OA is thought to be mediated by two main enzyme families: the MMP enzymes are responsible for cartilage collagen breakdown, whereas the enzymes from the ADAMTS family mediate cartilage aggrecan loss [57]. Overexpression of SIRT 1 in human chondrocytes leads to the repression of MMP 3, -8, and -13 and ADAMTS 4 gene expression, and down-regulating SIRT 1 leads to the induction of MMP 13 [58]. In human chondrocytes treated with IL-1β, SIRT 1 can play a protective role by suppressing IL-1β-induced expression of cartilage-degrading enzymes such as ADAMTS 5, MMP 1, 2, 9, and 13 partially through the modulation of the NF-κB (p65) pathway [59]. When chondrocytes are incubated with TNF-α, SIRT 1 also activates, deacetylates, and inactivates NF-κB p65 to exert an inhibitive effect on the expression of cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and MMPs [60]. In human chondrocytes, fisetin inhibits IL-1β-induced expression of nitric oxide (NO), PGE2, TNF-α, IL-6, COX-2, inducible nitric oxide synthase (iNOS), MMP 3, MMP 13, ADAMTS 5, and remarkably suppressed the degradation of SOX9, aggrecan, and collagen-II; it exerts all these anti-inflammatory effects through activating SIRT 1 [61]. Silencing of microRNA-449a shows a protective effect via targeting SIRT 1 to inhibit catabolic gene expression, restoring anabolic gene expression in IL-1β-induced cartilage destruction [62].

Anti-oxidative stress

SIRT 1 is strongly involved in the process of melatonin’s cytoprotective and anti-inflammatory effects in oxidative stress-stimulated chondrocytes. When oxidative stress induces senescence in chondrocytes, SIRT 1 enables chondrocytes to cope with unfavorable growing conditions. The mRNA of SIRT 1 was up-regulated after oxidant insult, but decreased in aging cells [63]. Expression of SIRT 1 could be induced by H2O2, and melatonin was confirmed to have the effect of decreasing SIRT 1 in chondrocytes [64]. Inhibiting SIRT 1 reversed the effects of melatonin on H2O2-mediated induction of proinflammatory cytokines (NO, PGE2, TNF-α, IL-1β, and IL-8) and the expression of iNOS and COX-2. Moreover, decreased SIRT 1 reversed the effects of melatonin, blocking the H2O2-induced phosphorylation of phosphoinositide 3-kinases (PI3K)/Akt, p38, ERK, C-Jun-N-terminal kinase (JNK), and mitogen-activated protein kinase (MAPK), as well as the activation of NF-κB [64]. In chondrocytes stimulated by oxidative stress, MiR-9 was identified and confirmed to be a post-transcriptional regulator of SIRT 1; MiR-9 silencing inhibits cell death, induced by H2O2 partly through down-regulation of SIRT 1 [65]. In H2O2-treated rat chondrocytes, rutin effectively inhibits the activation of inflammatory cytokines and MMP 2/9 by increasing SIRT 1, leading to the down-regulation of NF-kB/ MAPK, COX-2, and iNOS [28].

Anti-apoptosis and participation in autophagy

Autophagy participates in the OA development and regulates changes in OA-like gene expression through modulation of apoptosis and ROS as a protective process [66]. SIRT 1 is also in involved in this progress. Hydroxytyrosol stimulates autophagy and offers protection from oxidative stress-induced cell death in a SIRT 1-dependent manner by increasing p62 transcription [67]. SIRT 1 is an anti-apoptotic protein in human chondrocytes on account of its enzymatic activity: expression of SIRT 1 leads to activation of the insulin-like growth factor (IGF) receptor (IGFR) and the downstream kinases PI3K, pyruvate dehydrogenase kinase 1 (PDK1), mammalian target of rapamycin (mTOR), and Akt, ultimately resulting in the phosphorylation of mouse double minute 2 homolog (MDM2), inhibition of p53, and blocking apoptosis [37]. Furthermore, in human chondrocytes, SIRT 1 regulates apoptosis through the modulation of mitochondria-related apoptotic signals via translocation of Bax and Bcl-2 (SIRT 1 inhibition increases the amount of Bax and reduces the amount of Bcl-2). However, the increased NO-induced apoptosis by SIRT 1 inhibition is mediated by the activation of caspases 3 and 9, but is independent of the caspase 8 pathway [24]. Both AMPK and SIRT 1 are strong inducers of autophagy. Meanwhile, homeostasis of mitochondrial mass through mitochondrial is maintained through biogenesis and mitophagy. In human OA chondrocytes, mitochondrial biogenesis is deficient, which is linked to reduced AMPK activity and decreased expression of SIRT 1. Activation of the AMPK/SIRT-1/PGC-1a pathway reversed the impaired mitochondrial biogenesis capacity in cultured human OA chondrocytes [68]. The SIRT 1/p53 signaling pathway showed direct involvement in the miR-34a regulation, apoptosis, and inhibition of cell proliferation in human chondrocytes [69]. In the process of ionizing radiation (IR) induction of cellular senescence of chondrocytes, the role that IR plays is negative post-translational regulation of SIRT 1 via ROS-dependent p38 kinase activation; up-regulation of SIRT 1 distinctly reduces the IR-induced senescence phenotype and vice versa [70].

Other effects

In cartilage homeostasis, SIRT 1 also mediates the key clock gene expression with pathophysiological implications. In human knee OA cartilage, the levels of both NAD+ and Bmal 1, a circadian rhythm gene, were decreased significantly, resulting in the inhibition of NAMPT activity and SIRT 1 expression. Inhibition of SIRT 1 not only resulted in a reduction of Bmal1 and a moderate increase of period 2 (per2) and Rev-Erb α, but also further exacerbated the survival of cells with the expression of cartilage matrix-degrading enzymes induced by IL-1β [71].

OA affects all joint components, not only the cartilage, but also the bone, synovium, and so on. SIRT 1 also plays an important role in bone homeostasis. SIRT 1 is a genetic determinant of bone mass: the lack of SIRT 1 promotes osteoclastogenesis in osteoclasts in vitro and reduces osteoblast differentiation in osteoblasts through the control of NF-κB and bone cell differentiation [72]. Decreased SIRT 1 levels were found in human osteoarthritic subchondral osteoblasts [32]. In addition, Calcar SIRT 1 expression in the osteoporotic femoral neck (calcar region) was significantly reduced while sclerostin was markedly increased, showing that SIRT 1 and sclersotin expression are inversely correlated [73]. Inhibition of SIRT 1 in osteoblasts leads to increased transforming growth factor-β1 (TGF-β1) and sclerostin expression that decreases Wnt/β-catenin activity; conversely, the stimulation of SIRT 1 reduces the expression of TGF-β1 and sclerostin, as well as increases the mineralization in OA osteoblasts [73]. Wnt/β-catenin signaling is important for normal bone homeostasis and function; osteoblasts and osteoclasts are affected by decreased sclerostin, the inhibitor of the Wnt/β-catenin signaling, and a SIRT 1 target [32]. The expression and production of SIRT 1 were decreased in OA subchondral bone tissue [74]. SIRT 1 may regulate apoptosis and ECM degradation via the Wnt/β-catenin signaling pathway in OA chondrocytes [75]. SIRT 1 can regulate the bone marrow adipocyte phenotype, inducing a thermogenic gene program in mouse and human BM-MSCs via sclerostin inhibition [76]. Due to the relationship between SIRT 1 and Wnt/β-catenin signaling, the disruptor of telomeric silencing 1-like (DOT1L) could directly control Wnt signaling by inhibiting the activity of SIRT1, playing the role of safeguarding the homeostasis in cartilage and protecting against OA [77]. In the process of deletion of the oxygen sensor prolyl hydroxylase (PHD) 2 in osteocytes, the enhanced SIRT1 activates the WNT/β-catenin signaling and decreases the sclerostin, leading to increased osteoblast number and activity while decreasing osteoclastogenesis and bone resorption. However, the expression and effects of SIRT 1 in osteoarthritic subchondral bone and synovium needs to be further investigated, the related mechanism of SIRT 1 in OA was shown in Figure 1.

The mechanism of SIRT 1 and related pathway in OA

Figure 1
The mechanism of SIRT 1 and related pathway in OA

→ means there is a direct effect on the other, ↔ means there is an interaction between the both sides, ⇒ means there is an active effect on the other.

Figure 1
The mechanism of SIRT 1 and related pathway in OA

→ means there is a direct effect on the other, ↔ means there is an interaction between the both sides, ⇒ means there is an active effect on the other.

SIRT 1 in OA animal models

SIRT 1 has shown the ability to regulate the osteogenesis and adipogenesis of MSCs. MSC specific SIRT 1 knock-out (MSCKO) mice confirms that SIRT 1 regulates differentiation of MSCs by deacetylating β-catenin: MSCs isolated from MSCKO mice show reduced differentiation towards osteoblasts and chondrocytes in vitro [79]. In parathyroid hormone-related protein 1–84 [PTHrP(1–84)] knockin mice, Bmi-1 alters the BM-MSCs fate by enhancing osteoblast differentiation and inhibiting adipocyte differentiation, at least in part by stimulating SIRT 1 expression [80].

SIRT 1 and its enzymatic activity play a protective role in normal development and homeostasis of cartilage in vivo [81]. In the haploinsufficient SIRT 1 total body knockout (KO) mice, SIRT 1 KO mice exhibit cartilage defects that are consistent with their reduced size. SIRT 1 KO mice cartilage exhibit low levels of type II collagen, aggrecan, and glycosaminoglycan content in their paws; however, they exhibit elevated levels of MMP 13 and protein tyrosine phosphatase (PTP1B) in cartilage compamicroMred with wild-type (WT) mice [82]. Nevertheless, in the homozygous SIRT-1tm2.1Mcby (SIRT-1y/y) mice of OA models, the cartilage tissue changes are in line with previous reports. Moreover, bone defects (subchondral bone had less trabecular bone volume and thicker trabeculamicroM) and moderate local inflammations of the joint were also demonstrated in SIRT 1y/y mice [81]. In the SIRT 1−/− mice, MMP 13 and lymphoid enhancer-binding factor 1 (LEF1) appear to be elevated in the articular cartilage; activation of SIRT 1 plays a positive role in reducing the severity of OA, in part through its ability to repress the expression of MMPs [58]. Adult (9 month-old) heterozygous haploinsufficient SIRT 1 (+/−) mice showed decreased levels of aggrecan and other proteoglycans, but increased OA and levels of apoptosis compared with age-matched WT mice. Levels of full-length SIRT 1 were further decreased in both strains at 9 months. A 75 kDa SIRT 1 was found in 9-month-old WT mice; however, it was not detected in age-matched SIRT 1 (+/−) mice [83].

Activation SIRT 1 inhibits the OA progress via resveratrol

Resveratrol, a SIRT 1 activator, can protect chondrocytes against OA development. Resveratrol increased SIRT 1 protein expression in a dose-dependent manner: at concentrations of 25 and/or 50 µM, resveratrol treatment significantly up-regulates SIRT 1 gene expression in normal and osteoarthritic chondrocytes [84]. This was blocked by the SIRT 1 inhibitor, sirtinol, which inhibits TNF-α-induced inflammatory factor COX-2 and MMPs release, as well as ECM degradation [46], Resveratrol protects the chondrocytes from IL-1β stimulation in a dose-dependent manner via its activation of SIRT 1 [85]. The inhibition of SIRT 1 enhances NO-induced apoptosis of human chondrocytes, and resveratrol inhibits this NO-induced apoptosis. Resveratrol reduced the amount of Bax and increased the amount of Bcl-2 in the mitochondrial fraction [24]. In rabbit with OA, intra-articular injection of melatonin significantly reduced cartilage degradation, which was reversed by sirtinol [64].

In human chondrocytes, the overexpression of SIRT1 plays a protective role through the NF-kB pathway, reducing the up-regulation of MMP 1, 2, 9, 13, and ADAMTS 5 genes caused by IL-1b [59]. Moreover, up-regulation of SIRT1 or treatment with the SIRT1 activator resveratrol could affect NF-kB expression caused by TNF-a in order to exert an anti-inflammatory effect on human chondrocytes [60]. Meanwhile, the elevation of SIRT1 positively affects cartilage genes including collagen 2a, collagen 2b, and aggrecan expression [38]. SIRT 1 up-regulation could also suppress OA chondrocyte apoptosis and ECM degradation through increasing Bcl-2 and decreasing Bax, MMP 1, and MMP 13 expression via the inhibition of p38, JNK, and ERK phosphorylation [86].

In experimental OA mice, treatment with the SIRT1 activator SRT1720 could attenuate OA development though inhibiting synovitis, partially inhibiting the declined COL2A1 and aggrecan, and decreasing MMP 13, ADAMTS 5, cleaved caspase 3, PARP p85, and acetylated NF-κB p65-positive chondrocytes [87]. Silencing miR-449a leads to the up-regulation of SIRT 1, promoting cartilage regeneration and preventing progression of OA in rat models [88].

In a double-blind, randomized control trial which included 110 people with mild-to-moderate knee OA in Iraq, the patient–subjects received 15 mg meloxicam and either 500 mg resveratrol or placebo per day for 90 days. The results showed that the pain severity and serum levels of biochemical markers were significantly decreased in the resveratrol-treated group compared with the placebo-treated group [89]. The study further showed that resveratrol significantly improved function and associated symptoms. 500 mg/day of resveratrol was safe and well-tolerated by the knee OA patients [90]. In France, a protocol for a multicenter randomized double-blind placebo-controlled trial to evaluate the knee OA patients’ pain after 3 months of taking oral resveratrol was published but the proceedings and the results have yet to be determined [91]. Consequently, the therapeutic effects of resveratrol or other SIRT 1 activators in practice require further investigation and validation in clinical trials.

Conclusion

The greatest risk factor for OA is age. SIRT 1 is decreased with OA disease development in osteoarthritic cartilage. SIRT 1 can regulate ECM expression; promote MSCs differentiation; play anti-catabolic, anti-inflammatory, anti-oxidative stress, and anti-apoptosis roles; participate in the autophagic process; and regulate bone homeostasis in OA. Resveratrol activates SIRT 1 to inhibit the OA progress, in the future, activating SIRT 1 via resveratrol with better bioavailability may be an appropriate therapeutic approach for OA.

Availability of data and materials

All data generated or analyzed during the present study are included in this published article.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

This work was supported by the grants from the National Natural Science Foundation of China [grant number 81501923) and China Scholarship Council [student ID: 201606370164].

Abbreviations

     
  • ADAMTS

    a disintegrin and metalloproteinase with thrombospondin motifs

  •  
  • AMPK

    adenosine monophosphate-activated protein kinase

  •  
  • BM-MSCs

    bone marrow-derived mesenchymal stem cells

  •  
  • COX-2

    cyclooxygenase-2

  •  
  • DOT1L

    disruptor of telomeric silencing 1-like

  •  
  • ECM

    extracellular matrix

  •  
  • ERK

    extracellular signal-regulated kinases

  •  
  • FOXOs

    forkhead box transcription factor, class O

  •  
  • GlcN

    glucosamine

  •  
  • HSF 1

    heat shock factor 1

  •  
  • IGF

    insulin-like growth factor

  •  
  • IGFR

    insulin-like growth factor receptor

  •  
  • IL

    interleukin

  •  
  • iNOS

    inducible nitric oxide synthase

  •  
  • IR

    ionizing radiation

  •  
  • JNK

    C-Jun-N-terminal kinase

  •  
  • KO

    knock-out

  •  
  • LEF1

    lymphoid enhancer-binding factor 1

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • MDM2

    mouse double minute 2 homolog

  •  
  • MMP

    matrix metalloproteinase

  •  
  • MSC

    mesenchymal stem cell

  •  
  • mTOR

    mammalian target of rapamycin

  •  
  • NAD+

    nicotinamide adenine dinucleotide

  •  
  • NAMPT

    nicotinamide phosphoribosyltransferase

  •  
  • NF-κB

    nuclear factor-k-gene binding

  •  
  • NO

    nitric oxide

  •  
  • OA

    osteoarthitis

  •  
  • p53

    tumor protein p53

  •  
  • PDK1

    pyruvate dehydrogenase kinase 1

  •  
  • per2

    period 2

  •  
  • PGC-1

    PPARγ coactivator-1

  •  
  • PGE2

    prostaglandin E2

  •  
  • PHD

    prolyl hydroxylase

  •  
  • PI3K

    kinases phosphoinositide 3-kinases

  •  
  • PPARγ

    peroxisome proliferator-activated receptor γ

  •  
  • PTHrP(1-84)

    parathyroid hormone-related protein 1–84

  •  
  • PTP1B

    protein tyrosine phosphatase

  •  
  • ROS

    reactive oxygen species

  •  
  • RUNX2

    runt-related transcription factor 2

  •  
  • SIR 2

    silent information regulator 2

  •  
  • SIRT

    Sirtuin

  •  
  • SIRT 1

    Sirtuin 1

  •  
  • TGF-β1

    transforming growth factor-β1

  •  
  • TNF-α

    tumor necrosis factor-α

  •  
  • SOX9

    sex determining region Y box protein 9

  •  
  • Vav1

    vav guanine nucleotide exchange factor 1

  •  
  • WT

    wild-type

References

References
1.
Bennell
K.L.
,
Hunter
D.J.
and
Hinman
R.S.
(
2012
)
Management of osteoarthritis of the knee
.
BMJ
345
,
e4934
[PubMed]
2.
O’Neill
T.W.
,
McCabe
P.S.
and
McBeth
J.
(
2018
)
Update on the epidemiology, risk factors and disease outcomes of osteoarthritis
.
Best Pract. Res. Clin. Rheumatol.
32
,
312
326
[PubMed]
3.
Li
Y.S.
,
Xiao
W.F.
and
Luo
W.
(
2017
)
Cellular aging towards osteoarthritis
.
Mech. Ageing Dev.
162
,
80
84
[PubMed]
4.
Zhang
F.J.
,
Luo
W.
and
Lei
G.H.
(
2015
)
Role of HIF-1alpha and HIF-2alpha in osteoarthritis
.
Joint Bone Spine
82
,
144
147
[PubMed]
5.
Guarente
L.
(
2011
)
Franklin H. Epstein Lecture: sirtuins, aging, and medicine
.
N. Engl. J. Med.
364
,
2235
2244
[PubMed]
6.
Morris
B.J.
(
2013
)
Seven sirtuins for seven deadly diseases of aging
.
Free Radic. Biol. Med.
56
,
133
171
[PubMed]
7.
Imai
S.
and
Guarente
L.
(
2014
)
NAD+ and sirtuins in aging and disease
.
Trends Cell Biol.
24
,
464
471
[PubMed]
8.
Houtkooper
R.H.
,
Canto
C.
,
Wanders
R.J.
and
Auwerx
J.
(
2010
)
The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways
.
Endocr. Rev.
31
,
194
223
[PubMed]
9.
Li
X.
(
2013
)
SIRT1 and energy metabolism
.
Acta Biochim. Biophys. Sin.
45
,
51
60
[PubMed]
10.
Corbi
G.
,
Conti
V.
,
Scapagnini
G.
,
Filippelli
A.
and
Ferrara
N.
(
2012
)
Role of sirtuins, calorie restriction and physical activity in aging
.
Front Biosci.
4
,
768
778
[PubMed]
11.
Yacoub
R.
,
Lee
K.
and
He
J.C.
(
2014
)
The role of SIRT1 in diabetic kidney disease
.
Front Endocrinol.
5
,
166
[PubMed]
12.
Kida
Y.
and
Goligorsky
M.S.
(
2016
)
Sirtuins, cell senescence, and vascular aging
.
Can. J. Cardiol.
32
,
634
641
[PubMed]
13.
Tanner
K.G.
,
Landry
J.
,
Sternglanz
R.
and
Denu
J.M.
(
2000
)
Silent information regulator 2 family of NAD- dependent histone/protein deacetylases generates a unique product, 1-O-acetyl-ADP-ribose
.
Proc. Natl. Acad. Sci. U.S.A.
97
,
14178
14182
14.
Gabay
O.
and
Clouse
K.A.
(
2016
)
Epigenetics of cartilage diseases
.
Joint Bone Spine
83
,
491
494
[PubMed]
15.
Michan
S.
and
Sinclair
D.
(
2007
)
Sirtuins in mammals: insights into their biological function
.
Biochem. J.
404
,
1
13
[PubMed]
16.
Nemoto
S.
,
Fergusson
M.M.
and
Finkel
T.
(
2004
)
Nutrient availability regulates SIRT1 through a forkhead-dependent pathway
.
Science
306
,
2105
2108
[PubMed]
17.
Kaeberlein
M.
,
McDonagh
T.
,
Heltweg
B.
,
Hixon
J.
,
Westman
E.A.
,
Caldwell
S.D.
et al.
(
2005
)
Substrate-specific activation of sirtuins by resveratrol
.
J. Biol. Chem.
280
,
17038
17045
[PubMed]
18.
Alcain
F.J.
and
Villalba
J.M.
(
2009
)
Sirtuin activators
.
Expert Opin. Ther. Pat.
19
,
403
414
[PubMed]
19.
Borra
M.T.
,
Smith
B.C.
and
Denu
J.M.
(
2005
)
Mechanism of human SIRT1 activation by resveratrol
.
J. Biol. Chem.
280
,
17187
17195
[PubMed]
20.
Milner
P.I.
,
Fairfax
T.P.
,
Browning
J.A.
,
Wilkins
R.J.
and
Gibson
J.S.
(
2006
)
The effect of O2 tension on pH homeostasis in equine articular chondrocytes
.
Arthritis Rheum.
54
,
3523
3532
[PubMed]
21.
Deng
Z.H.
,
Li
Y.S.
,
Gao
X.
,
Lei
G.H.
and
Huard
J.
(
2018
)
Bone morphogenetic proteins for articular cartilage regeneration
.
Osteoarthritis Cartilage
26
,
1153
1161
[PubMed]
22.
Loeser
R.F.
(
2009
)
Aging and osteoarthritis: the role of chondrocyte senescence and aging changes in the cartilage matrix
.
Osteoarthritis Cartilage
17
,
971
979
[PubMed]
23.
Li
Y.S.
,
Luo
W.
,
Zhu
S.A.
and
Lei
G.H.
(
2017
)
T Cells in Osteoarthritis: alterations and beyond
.
Front Immunol.
8
,
356
[PubMed]
24.
Takayama
K.
,
Ishida
K.
,
Matsushita
T.
,
Fujita
N.
,
Hayashi
S.
,
Sasaki
K.
et al.
(
2009
)
SIRT1 regulation of apoptosis of human chondrocytes
.
Arthritis Rheum.
60
,
2731
2740
[PubMed]
25.
Niederer
F.
,
Ospelt
C.
,
Brentano
F.
,
Hottiger
M.O.
,
Gay
R.E.
,
Gay
S.
et al.
(
2011
)
SIRT1 overexpression in the rheumatoid arthritis synovium contributes to proinflammatory cytokine production and apoptosis resistance
.
Ann. Rheum. Dis.
70
,
1866
1873
[PubMed]
26.
Dvir-Ginzberg
M.
,
Gagarina
V.
,
Lee
E.J.
,
Booth
R.
,
Gabay
O.
and
Hall
D.J.
(
2011
)
Tumor necrosis factor alpha-mediated cleavage and inactivation of SirT1 in human osteoarthritic chondrocytes
.
Arthritis Rheum.
63
,
2363
2373
[PubMed]
27.
Hwang
J.W.
,
Yao
H.
,
Caito
S.
,
Sundar
I.K.
and
Rahman
I.
(
2013
)
Redox regulation of SIRT1 in inflammation and cellular senescence
.
Free Radic. Biol. Med.
61
,
95
110
[PubMed]
28.
Na
J.Y.
,
Song
K.
,
Kim
S.
and
Kwon
J.
(
2016
)
Rutin protects rat articular chondrocytes against oxidative stress induced by hydrogen peroxide through SIRT1 activation
.
Biochem. Biophys. Res. Commun.
473
,
1301
1308
[PubMed]
29.
Qiu
L.
,
Luo
Y.
and
Chen
X.
(
2018
)
Quercetin attenuates mitochondrial dysfunction and biogenesis via upregulated AMPK/SIRT1 signaling pathway in OA rats
.
Biomed. Pharmacother.
103
,
1585
1591
[PubMed]
30.
Fujita
N.
,
Matsushita
T.
,
Ishida
K.
,
Kubo
S.
,
Matsumoto
T.
,
Takayama
K.
et al.
(
2011
)
Potential involvement of SIRT1 in the pathogenesis of osteoarthritis through the modulation of chondrocyte gene expressions
.
J. Orthop. Res.
29
,
511
515
[PubMed]
31.
Li
Y.
,
Xiao
W.
,
Wu
P.
,
Deng
Z.
,
Zeng
C.
,
Li
H.
et al.
(
2016
)
The expression of SIRT1 in articular cartilage of patients with knee osteoarthritis and its correlation with disease severity
.
J. Orthop. Surg. Res.
11
,
144
[PubMed]
32.
Abed
E.
,
Couchourel
D.
,
Delalandre
A.
,
Duval
N.
,
Pelletier
J.P.
,
Martel-Pelletier
J.
et al.
(
2014
)
Low sirtuin 1 levels in human osteoarthritis subchondral osteoblasts lead to abnormal sclerostin expression which decreases Wnt/beta-catenin activity
.
Bone
59
,
28
36
[PubMed]
33.
Wendling
D.
,
Abbas
W.
,
Godfrin-Valnet
M.
,
Guillot
X.
,
Khan
K.A.
,
Cedoz
J.P.
et al.
(
2013
)
Resveratrol, a sirtuin 1 activator, increases IL-6 production by peripheral blood mononuclear cells of patients with knee osteoarthritis
.
Clin. Epigenetics
5
,
10
[PubMed]
34.
Matsuzaki
T.
,
Matsushita
T.
,
Takayama
K.
,
Matsumoto
T.
,
Nishida
K.
,
Kuroda
R.
et al.
(
2014
)
Disruption of Sirt1 in chondrocytes causes accelerated progression of osteoarthritis under mechanical stress and during ageing in mice
.
Ann. Rheum. Dis.
73
,
1397
1404
[PubMed]
35.
Oppenheimer
H.
,
Gabay
O.
,
Meir
H.
,
Haze
A.
,
Kandel
L.
,
Liebergall
M.
et al.
(
2012
)
75-kd sirtuin 1 blocks tumor necrosis factor alpha-mediated apoptosis in human osteoarthritic chondrocytes
.
Arthritis Rheum.
64
,
718
728
[PubMed]
36.
Gabay
O.
and
Sanchez
C.
(
2012
)
Epigenetics, sirtuins and osteoarthritis
.
Joint Bone Spine
79
,
570
573
[PubMed]
37.
Gagarina
V.
,
Gabay
O.
,
Dvir-Ginzberg
M.
,
Lee
E.J.
,
Brady
J.K.
,
Quon
M.J.
et al.
(
2010
)
SirT1 enhances survival of human osteoarthritic chondrocytes by repressing protein tyrosine phosphatase 1B and activating the insulin-like growth factor receptor pathway
.
Arthritis Rheum.
62
,
1383
1392
[PubMed]
38.
Dvir-Ginzberg
M.
,
Gagarina
V.
,
Lee
E.J.
and
Hall
D.J.
(
2008
)
Regulation of cartilage-specific gene expression in human chondrocytes by SirT1 and nicotinamide phosphoribosyltransferase
.
J. Biol. Chem.
283
,
36300
36310
[PubMed]
39.
Oppenheimer
H.
,
Kumar
A.
,
Meir
H.
,
Schwartz
I.
,
Zini
A.
,
Haze
A.
et al.
(
2014
)
Set7/9 impacts COL2A1 expression through binding and repression of SirT1 histone deacetylation
.
J. Bone Miner. Res.
29
,
348
360
[PubMed]
40.
Igarashi
M.
,
Sakamoto
K.
and
Nagaoka
I.
(
2017
)
Effect of glucosamine on expression of type II collagen, matrix metalloproteinase and sirtuin genes in a human chondrocyte cell line
.
Int. J. Mol. Med.
39
,
472
478
[PubMed]
41.
Buhrmann
C.
,
Busch
F.
,
Shayan
P.
and
Shakibaei
M.
(
2014
)
Sirtuin-1 (SIRT1) is required for promoting chondrogenic differentiation of mesenchymal stem cells
.
J. Biol. Chem.
289
,
22048
22062
[PubMed]
42.
Lefebvre
V.
and
Dvir-Ginzberg
M.
(
2017
)
SOX9 and the many facets of its regulation in the chondrocyte lineage
.
Connect. Tissue Res.
58
,
2
14
[PubMed]
43.
Terauchi
K.
,
Kobayashi
H.
,
Yatabe
K.
,
Yui
N.
,
Fujiya
H.
,
Niki
H.
et al.
(
2016
)
The NAD-dependent deacetylase sirtuin-1 regulates the expression of osteogenic transcriptional activator runt-related transcription factor 2 (Runx2) and production of matrix metalloproteinase (MMP)-13 in chondrocytes in osteoarthritis
.
Int. J. Mol. Sci.
17
44.
Qu
P.
,
Wang
L.
,
Min
Y.
,
McKennett
L.
,
Keller
J.R.
and
Lin
P.C.
(
2016
)
Vav1 regulates mesenchymal stem cell differentiation decision between adipocyte and chondrocyte via Sirt1
.
Stem Cells
34
,
1934
1946
[PubMed]
45.
Bar
O.M.
,
Kumar
A.
,
Elayyan
J.
,
Reich
E.
,
Binyamin
M.
,
Kandel
L.
et al.
(
2016
)
Acetylation reduces SOX9 nuclear entry and ACAN gene transactivation in human chondrocytes
.
Aging Cell
15
,
499
508
[PubMed]
46.
Hong
E.H.
,
Yun
H.S.
,
Kim
J.
,
Um
H.D.
,
Lee
K.H.
,
Kang
C.M.
et al.
(
2011
)
Nicotinamide phosphoribosyltransferase is essential for interleukin-1beta-mediated dedifferentiation of articular chondrocytes via SIRT1 and extracellular signal-regulated kinase (ERK) complex signaling
.
J. Biol. Chem.
286
,
28619
28631
[PubMed]
47.
Li
M.
,
Yan
J.
,
Chen
X.
,
Tam
W.
,
Zhou
L.
,
Liu
T.
et al.
(
2018
)
Spontaneous up-regulation of SIRT1 during osteogenesis contributes to stem cells’ resistance to oxidative stress
.
J. Cell. Biochem.
119
,
4928
4944
[PubMed]
48.
Lin
C.H.
,
Li
N.T.
,
Cheng
H.S.
and
Yen
M.L.
(
2018
)
Oxidative stress induces imbalance of adipogenic/osteoblastic lineage commitment in mesenchymal stem cells through decreasing SIRT1 functions
.
J. Cell. Mol. Med.
22
,
786
796
[PubMed]
49.
Yu
F.
,
Yuan
Y.
,
Li
D.
,
Kou
Y.
,
Jiang
B.
and
Zhang
P.
(
2019
)
The effect of lentivirus-mediated SIRT1 gene knockdown in the ATDC5 cell line via inhibition of the Wnt signaling pathway
.
Cell. Signal.
53
,
80
89
[PubMed]
50.
Zhou
Y.
,
Song
T.
,
Peng
J.
,
Zhou
Z.
,
Wei
H.
,
Zhou
R.
et al.
(
2016
)
SIRT1 suppresses adipogenesis by activating Wnt/beta-catenin signaling in vivo and in vitro
.
Oncotarget
7
,
77707
77720
[PubMed]
51.
Zhou
Y.
,
Zhou
Z.
,
Zhang
W.
,
Hu
X.
,
Wei
H.
,
Peng
J.
et al.
(
2015
)
SIRT1 inhibits adipogenesis and promotes myogenic differentiation in C3H10T1/2 pluripotent cells by regulating Wnt signaling
.
Cell Biosci.
5
,
61
[PubMed]
52.
Chen
X.
,
Yan
J.
,
He
F.
,
Zhong
D.
,
Yang
H.
,
Pei
M.
et al.
(
2018
)
Mechanical stretch induces antioxidant responses and osteogenic differentiation in human mesenchymal stem cells through activation of the AMPK-SIRT1 signaling pathway
.
Free Radic. Biol. Med.
126
,
187
201
[PubMed]
53.
Wang
H.
,
Hu
Z.
,
Wu
J.
,
Mei
Y.
,
Zhang
Q.
,
Zhang
H.
et al.
(
2019
)
Sirt1 promotes osteogenic differentiation and increases alveolar bone mass via Bmi1 activation in mice
.
J. Bone Miner. Res.
e3677
[PubMed]
54.
Khanh
V.C.
,
Zulkifli
A.F.
,
Tokunaga
C.
,
Yamashita
T.
,
Hiramatsu
Y.
and
Ohneda
O.
(
2018
)
Aging impairs beige adipocyte differentiation of mesenchymal stem cells via the reduced expression of Sirtuin 1
.
Biochem. Biophys. Res. Commun.
500
,
682
690
[PubMed]
55.
Kapoor
M.
,
Martel-Pelletier
J.
,
Lajeunesse
D.
,
Pelletier
J.P.
and
Fahmi
H.
(
2011
)
Role of proinflammatory cytokines in the pathophysiology of osteoarthritis
.
Nat. Rev. Rheumatol.
7
,
33
42
[PubMed]
56.
Goldring
M.B.
and
Marcu
K.B.
(
2009
)
Cartilage homeostasis in health and rheumatic diseases
.
Arthritis Res. Ther.
11
,
224
[PubMed]
57.
Davidson
R.K.
,
Waters
J.G.
,
Kevorkian
L.
,
Darrah
C.
,
Cooper
A.
,
Donell
S.T.
et al.
(
2006
)
Expression profiling of metalloproteinases and their inhibitors in synovium and cartilage
.
Arthritis Res. Ther.
8
,
R124
[PubMed]
58.
Elayyan
J.
,
Lee
E.J.
,
Gabay
O.
,
Smith
C.A.
,
Qiq
O.
,
Reich
E.
et al.
(
2017
)
LEF1-mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes
.
FASEB J.
31
,
3116
3125
[PubMed]
59.
Matsushita
T.
,
Sasaki
H.
,
Takayama
K.
,
Ishida
K.
,
Matsumoto
T.
,
Kubo
S.
et al.
(
2013
)
The overexpression of SIRT1 inhibited osteoarthritic gene expression changes induced by interleukin-1beta in human chondrocytes
.
J. Orthop. Res.
31
,
531
537
[PubMed]
60.
Moon
M.H.
,
Jeong
J.K.
,
Lee
Y.J.
,
Seol
J.W.
,
Jackson
C.J.
and
Park
S.Y.
(
2013
)
SIRT1, a class III histone deacetylase, regulates TNF-alpha-induced inflammation in human chondrocytes
.
Osteoarthritis Cartilage
21
,
470
480
[PubMed]
61.
Zheng
W.
,
Feng
Z.
,
You
S.
,
Zhang
H.
,
Tao
Z.
,
Wang
Q.
et al.
(
2017
)
Fisetin inhibits IL-1beta-induced inflammatory response in human osteoarthritis chondrocytes through activating SIRT1 and attenuates the progression of osteoarthritis in mice
.
Int. Immunopharmacol.
45
,
135
147
[PubMed]
62.
Park
K.W.
,
Lee
K.M.
,
Yoon
D.S.
,
Park
K.H.
,
Choi
W.J.
,
Lee
J.W.
et al.
(
2016
)
Inhibition of microRNA-449a prevents IL-1beta-induced cartilage destruction via SIRT1
.
Osteoarthritis Cartilage
24
,
2153
2161
[PubMed]
63.
Brandl
A.
,
Hartmann
A.
,
Bechmann
V.
,
Graf
B.
,
Nerlich
M.
and
Angele
P.
(
2011
)
Oxidative stress induces senescence in chondrocytes
.
J. Orthop. Res.
29
,
1114
1120
[PubMed]
64.
Lim
H.D.
,
Kim
Y.S.
,
Ko
S.H.
,
Yoon
I.J.
,
Cho
S.G.
,
Chun
Y.H.
et al.
(
2012
)
Cytoprotective and anti-inflammatory effects of melatonin in hydrogen peroxide-stimulated CHON-001 human chondrocyte cell line and rabbit model of osteoarthritis via the SIRT1 pathway
.
J. Pineal Res.
53
,
225
237
[PubMed]
65.
D’Adamo
S.
,
Cetrullo
S.
,
Guidotti
S.
,
Borzi
R.M.
and
Flamigni
F.
(
2017
)
Hydroxytyrosol modulates the levels of microRNA-9 and its target sirtuin-1 thereby counteracting oxidative stress-induced chondrocyte death
.
Osteoarthritis Cartilage
25
,
600
610
[PubMed]
66.
Li
Y.S.
,
Zhang
F.J.
,
Zeng
C.
,
Luo
W.
,
Xiao
W.F.
,
Gao
S.G.
et al.
(
2016
)
Autophagy in osteoarthritis
.
Joint Bone Spine
83
,
143
148
[PubMed]
67.
Cetrullo
S.
,
D’Adamo
S.
,
Guidotti
S.
,
Borzi
R.M.
and
Flamigni
F.
(
2016
)
Hydroxytyrosol prevents chondrocyte death under oxidative stress by inducing autophagy through sirtuin 1-dependent and -independent mechanisms
.
Biochim. Biophys. Acta
1860
,
1181
1191
[PubMed]
68.
Wang
Y.
,
Zhao
X.
,
Lotz
M.
,
Terkeltaub
R.
and
Liu-Bryan
R.
(
2015
)
Mitochondrial biogenesis is impaired in osteoarthritis chondrocytes but reversible via peroxisome proliferator-activated receptor gamma coactivator 1alpha
.
Arthritis Rheumatol.
67
,
2141
2153
[PubMed]
69.
Yan
S.
,
Wang
M.
,
Zhao
J.
,
Zhang
H.
,
Zhou
C.
,
Jin
L.
et al.
(
2016
)
MicroRNA-34a affects chondrocyte apoptosis and proliferation by targeting the SIRT1/p53 signaling pathway during the pathogenesis of osteoarthritis
.
Int. J. Mol. Med.
38
,
201
209
[PubMed]
70.
Hong
E.H.
,
Lee
S.J.
,
Kim
J.S.
,
Lee
K.H.
,
Um
H.D.
,
Kim
J.H.
et al.
(
2010
)
Ionizing radiation induces cellular senescence of articular chondrocytes via negative regulation of SIRT1 by p38 kinase
.
J. Biol. Chem.
285
,
1283
1295
[PubMed]
71.
Yang
W.
,
Kang
X.
,
Liu
J.
,
Li
H.
,
Ma
Z.
,
Jin
X.
et al.
(
2016
)
Clock gene Bmal1 modulates human cartilage gene expression by crosstalk with sirt1
.
Endocrinology
157
,
3096
3107
[PubMed]
72.
Edwards
J.R.
,
Perrien
D.S.
,
Fleming
N.
,
Nyman
J.S.
,
Ono
K.
,
Connelly
L.
et al.
(
2013
)
Silent information regulator (Sir)T1 inhibits NF-kappaB signaling to maintain normal skeletal remodeling
.
J. Bone Miner. Res.
28
,
960
969
[PubMed]
73.
El-Haj
M.
,
Gurt
I.
,
Cohen-Kfir
E.
,
Dixit
V.
,
Artsi
H.
,
Kandel
L.
et al.
(
2016
)
Reduced Sirtuin1 expression at the femoral neck in women who sustained an osteoporotic hip fracture
.
Osteoporos. Int.
27
,
2373
2378
[PubMed]
74.
Abed
E.
,
Delalandre
A.
and
Lajeunesse
D.
(
2017
)
Beneficial effect of resveratrol on phenotypic features and activity of osteoarthritic osteoblasts
.
Arthritis Res. Ther.
19
,
151
[PubMed]
75.
Liu
S.
,
Yang
H.
,
Hu
B.
and
Zhang
M.
(
2017
)
Sirt1 regulates apoptosis and extracellular matrix degradation in resveratrol-treated osteoarthritis chondrocytes via the Wnt/beta-catenin signaling pathways
.
Exp. Ther. Med.
14
,
5057
5062
[PubMed]
76.
Artsi
H.
,
Gurt
I.
,
El-Haj
M.
,
Muller
R.
,
Kuhn
G.A.
,
Ben
S.G.
et al.
(
2019
)
Sirt1 promotes a thermogenic gene program in bone marrow adipocytes: from mice to (wo)men
.
Front Endocrinol.
10
,
126
[PubMed]
77.
Monteagudo
S.
,
Cornelis
F.
,
Aznar-Lopez
C.
,
Yibmantasiri
P.
,
Guns
L.A.
,
Carmeliet
P.
et al.
(
2017
)
DOT1L safeguards cartilage homeostasis and protects against osteoarthritis
.
Nat. Commun.
8
,
15889
[PubMed]
78.
Stegen
S.
,
Stockmans
I.
,
Moermans
K.
,
Thienpont
B.
,
Maxwell
P.H.
,
Carmeliet
P.
et al.
(
2018
)
Osteocytic oxygen sensing controls bone mass through epigenetic regulation of sclerostin
.
Nat. Commun.
9
,
2557
[PubMed]
79.
Simic
P.
,
Zainabadi
K.
,
Bell
E.
,
Sykes
D.B.
,
Saez
B.
,
Lotinun
S.
et al.
(
2013
)
SIRT1 regulates differentiation of mesenchymal stem cells by deacetylating beta-catenin
.
Embo. Mol. Med.
5
,
430
440
[PubMed]
80.
Zhang
H.W.
,
Ding
J.
,
Jin
J.L.
,
Guo
J.
,
Liu
J.N.
,
Karaplis
A.
et al.
(
2010
)
Defects in mesenchymal stem cell self-renewal and cell fate determination lead to an osteopenic phenotype in Bmi-1 null mice
.
J. Bone Miner. Res.
25
,
640
652
[PubMed]
81.
Gabay
O.
,
Sanchez
C.
,
Dvir-Ginzberg
M.
,
Gagarina
V.
,
Zaal
K.J.
,
Song
Y.
et al.
(
2013
)
Sirtuin 1 enzymatic activity is required for cartilage homeostasis in vivo in a mouse model
.
Arthritis Rheum.
65
,
159
166
[PubMed]
82.
Gabay
O.
,
Zaal
K.J.
,
Sanchez
C.
,
Dvir-Ginzberg
M.
,
Gagarina
V.
,
Song
Y.
et al.
(
2013
)
Sirt1-deficient mice exhibit an altered cartilage phenotype
.
Joint Bone Spine
80
,
613
620
[PubMed]
83.
Gabay
O.
,
Oppenhiemer
H.
,
Meir
H.
,
Zaal
K.
,
Sanchez
C.
and
Dvir-Ginzberg
M.
(
2012
)
Increased apoptotic chondrocytes in articular cartilage from adult heterozygous SirT1 mice
.
Ann. Rheum. Dis.
71
,
613
616
[PubMed]
84.
Kim
H.J.
,
Braun
H.J.
and
Dragoo
J.L.
(
2014
)
The effect of resveratrol on normal and osteoarthritic chondrocyte metabolism
.
Bone Joint Res
3
,
51
59
[PubMed]
85.
Lei
M.
,
Wang
J.G.
,
Xiao
D.M.
,
Fan
M.
,
Wang
D.P.
,
Xiong
J.Y.
et al.
(
2012
)
Resveratrol inhibits interleukin 1beta-mediated inducible nitric oxide synthase expression in articular chondrocytes by activating SIRT1 and thereby suppressing nuclear factor-kappaB activity
.
Eur. J. Pharmacol.
674
,
73
79
[PubMed]
86.
He
D.S.
,
Hu
X.J.
,
Yan
Y.Q.
and
Liu
H.
(
2017
)
Underlying mechanism of Sirt1 on apoptosis and extracellular matrix degradation of osteoarthritis chondrocytes
.
Mol. Med. Rep.
16
,
845
850
[PubMed]
87.
Nishida
K.
,
Matsushita
T.
,
Takayama
K.
,
Tanaka
T.
,
Miyaji
N.
,
Ibaraki
K.
et al.
(
2018
)
Intraperitoneal injection of the SIRT1 activator SRT1720 attenuates the progression of experimental osteoarthritis in mice
.
Bone Joint Res.
7
,
252
262
[PubMed]
88.
Baek
D.
,
Lee
K.M.
,
Park
K.W.
,
Suh
J.W.
,
Choi
S.M.
,
Park
K.H.
et al.
(
2018
)
Inhibition of miR-449a promotes cartilage regeneration and prevents progression of osteoarthritis in in vivo rat models
.
Mol. Ther. Nucleic Acids
13
,
322
333
[PubMed]
89.
Marouf
B.H.
,
Hussain
S.A.
,
Ali
Z.S.
and
Ahmmad
R.S.
(
2018
)
Resveratrol supplementation reduces pain and inflammation in knee osteoarthritis patients treated with meloxicam: a randomized placebo-controlled study
.
J. Med. Food
[PubMed]
90.
Hussain
S.A.
,
Marouf
B.H.
,
Ali
Z.S.
and
Ahmmad
R.S.
(
2018
)
Efficacy and safety of co-administration of resveratrol with meloxicam in patients with knee osteoarthritis: a pilot interventional study
.
Clin. Interv. Aging
13
,
1621
1630
[PubMed]
91.
Nguyen
C.
,
Boutron
I.
,
Baron
G.
,
Coudeyre
E.
,
Berenbaum
F.
,
Poiraudeau
S.
et al.
(
2017
)
Evolution of pain at 3 months by oral resveratrol in knee osteoarthritis (ARTHROL): protocol for a multicentre randomised double-blind placebo-controlled trial
.
BMJ Open
7
,
e17652

Author notes

*

These authors contributed equally to this work.

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