Depletion of SIRT6 causes cellular senescence, DNA damage, and telomere dysfunction in human chondrocytes.

Abstract:

OBJECTIVE:SIRT6, a member of the sirtuin family of nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacetylases, has been implicated as a key factor in aging-related diseases. However, the role of SIRT6 in chondrocytes has not been fully explored. The purpose of this study was to examine the role of SIRT6 in human chondrocytes by inhibiting SIRT6 in vitro. DESIGN:First, the localization of SIRT6 and proliferation cell nuclear antigen (PCNA) in human cartilages was examined by immunohistochemistry. Next, SIRT6 was depleted by RNA interference (RNAi), and the effect of SIRT6 depletion on changes in gene expression, protein levels, proliferation, and senescence in human chondrocytes was assessed. Furthermore, to detect DNA damage and telomere dysfunction, γH2AX foci and telomere dysfunction-induced foci (TIFs) were examined using immunofluorescence microscopy. The protein levels of two mediators for DNA damage induced-senescence, p16 and p21, were examined by western blotting. RESULTS:Immunohistochemical analysis showed SIRT6 was preferentially expressed in the superficial zone chondrocytes and PCNA-positive cluster-forming chondrocytes in the osteoarthritic cartilage tissue samples. Real-time PCR analysis showed that matrix metalloproteinase 1 (MMP-1) and MMP-13 mRNA were significantly increased by SIRT6 inhibition. Moreover, SIRT6 inhibition significantly reduced proliferation and increased senescence associated β-galactosidase (SA-β-Gal)-positive chondrocytes; it also led to increased p16 levels. Immunofluorescence microscopy showed that γH2AX foci and TIFs were increased by SIRT6 inhibition. CONCLUSION:Depletion of SIRT6 in human chondrocytes caused increased DNA damage and telomere dysfunction, and subsequent premature senescence. These findings suggest that SIRT6 plays an important role in the regulation of senescence of human chondrocytes.

authors

Nagai K,Matsushita T,Matsuzaki T,Takayama K,Matsumoto T,Kuroda R,Kurosaka M

doi

10.1016/j.joca.2015.03.024

subject

Has Abstract

pub_date

2015-08-01 00:00:00

pages

1412-20

issue

8

eissn

1063-4584

issn

1522-9653

pii

S1063-4584(15)00866-3

journal_volume

23

pub_type

杂志文章
  • Loss of Vhl in cartilage accelerated the progression of age-associated and surgically induced murine osteoarthritis.

    abstract:OBJECTIVE:To investigate the role of Vhl in maintaining the integrity of articular cartilage and in the development of experimental osteoarthritis (OA). METHOD:Histology of articular cartilage and subchondral bone in both Vhl cKO and WT mice were analyzed by histopathology and micro-CT. Articular cartilage destruction...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章

    doi:10.1016/j.joca.2014.06.031

    authors: Weng T,Xie Y,Yi L,Huang J,Luo F,Du X,Chen L,Liu C,Chen D,Chen L

    更新日期:2014-08-01 00:00:00

  • Methodologic issues in clinical trials for prevention or risk reduction in osteoarthritis.

    abstract::The design and execution of prevention trials for OA have methodological issues that are distinct from trials designed to impact prevalent disease. Disease definitions and their precise and sensitive measurement, identification of high-risk populations, the nature of the intervention (pharmaceutical, nutraceutical, be...

    journal_title:Osteoarthritis and cartilage

    pub_type: 共识发展会议,杂志文章

    doi:10.1016/j.joca.2010.10.031

    authors: Jordan JM,Sowers MF,Messier SP,Bradley J,Arangio G,Katz JN,Losina E,Rovati L,Bachtell N,Cooper C,Spector T,Zhang W,Gardiner J,Wahba M

    更新日期:2011-05-01 00:00:00

  • ADAMTS and ADAM metalloproteinases in osteoarthritis - looking beyond the 'usual suspects'.

    abstract:INTRODUCTION:Matrix metalloproteinases (MMPs) and 'aggrecanase' a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) are well established to play key roles in osteoarthritis (OA) through degradation of extracellular matrix (ECM) type II collagen and aggrecan, and are thus potential targets for devel...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章,评审

    doi:10.1016/j.joca.2017.02.791

    authors: Yang CY,Chanalaris A,Troeberg L

    更新日期:2017-07-01 00:00:00

  • Effects of treadmill running and limb immobilization on knee cartilage degeneration and locomotor joint kinematics in rats following knee meniscal transection.

    abstract:OBJECTIVE:This study examined the effects of reduced and elevated weight bearing on post-traumatic osteoarthritis (PTOA) development, locomotor joint kinematics, and degree of voluntary activity in rats following medial meniscal transection (MMT). DESIGN:Twenty-one adult rats were subjected to MMT surgery of the left ...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章

    doi:10.1016/j.joca.2019.08.001

    authors: Tsai LC,Cooper ES,Hetzendorfer KM,Warren GL,Chang YH,Willett NJ

    更新日期:2019-12-01 00:00:00

  • Preferences for physical activity: a conjoint analysis involving people with chronic knee pain.

    abstract:OBJECTIVE:To investigate individual preferences for physical activity (PA) attributes in adults with chronic knee pain, to identify clusters of individuals with similar preferences, and to identify whether individuals in these clusters differ by their demographic and health characteristics. DESIGN:An adaptive conjoint...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章,多中心研究

    doi:10.1016/j.joca.2018.10.002

    authors: Pinto D,Bockenholt U,Lee J,Chang RW,Sharma L,Finn DJ,Heinemann AW,Holl JL,Hansen P

    更新日期:2019-02-01 00:00:00

  • OARSI Clinical Trials Recommendations: An abbreviated regulatory guide to the clinical requirements for development of therapeutics in osteoarthritis.

    abstract::In this brief abbreviated review of regulatory issues regarding the development of drugs and or devices for the treatment of osteoarthritis (OA), the steps that are expected by both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) are discussed. ...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章,评审

    doi:10.1016/j.joca.2015.03.010

    authors: Simon LS

    更新日期:2015-05-01 00:00:00

  • The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse.

    abstract:OBJECTIVE:To evaluate anterior cruciate ligament transection (ACLT) and destabilization of the medial meniscus (DMM) surgical instability models of osteoarthritis (OA) in the 129/SvEv mouse knee joint. DESIGN:Micro-surgical techniques were used to perform ACLT or DMM under direct visualization. Histological scoring wa...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章

    doi:10.1016/j.joca.2007.03.006

    authors: Glasson SS,Blanchet TJ,Morris EA

    更新日期:2007-09-01 00:00:00

  • The evolving large-strain shear responses of progressively osteoarthritic human cartilage.

    abstract:OBJECTIVE:The composition and structure of articular cartilage evolves during the development and progression of osteoarthritis (OA) resulting in changing mechanical responses. We aimed to assess the evolution of the intrinsic, large-strain mechanics of human articular cartilage-governed by collagen and proteoglycan an...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章

    doi:10.1016/j.joca.2018.12.025

    authors: Maier F,Lewis CG,Pierce DM

    更新日期:2019-05-01 00:00:00

  • Comparative evaluation of three semi-quantitative radiographic grading techniques for hip osteoarthritis in terms of validity and reproducibility in 1404 radiographs: report of the OARSI-OMERACT Task Force.

    abstract:OBJECTIVE:The objective of this work was to compare the measurement properties of three categorical X-ray scoring methods for hip osteoarthritis (OA). METHODS:In data obtained from trials and cohorts, radiographs were evaluated using the Kellgren and Lawrence (KL) grading system, the Osteoarthritis Research Society In...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章

    doi:10.1016/j.joca.2008.06.009

    authors: Gossec L,Jordan JM,Lam MA,Fang F,Renner JB,Davis A,Hawker GA,Dougados M,Maillefert JF,OARSI-OMERACT task force \total articular replacement as outcome measure in OA\.

    更新日期:2009-02-01 00:00:00

  • Identification and pharmacological characterization of a novel inhibitor of autotaxin in rodent models of joint pain.

    abstract:OBJECTIVE:Autotaxin is a secreted lysophospholipase that mediates the conversion of lysophosphatidyl choline (LPC) to lysophosphatidic acid (LPA), a bioactive lipid mediator. Autotaxin levels in plasma and synovial fluid correlate with disease severity in patients with knee osteoarthritis (OA). The goal of this study w...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章

    doi:10.1016/j.joca.2016.09.006

    authors: Thirunavukkarasu K,Swearingen CA,Oskins JL,Lin C,Bui HH,Jones SB,Pfeifer LA,Norman BH,Mitchell PG,Chambers MG

    更新日期:2017-06-01 00:00:00

  • Bone marrow stimulation induces greater chondrogenesis in trochlear vs condylar cartilage defects in skeletally mature rabbits.

    abstract:OBJECTIVE:The aim of this study was to compare the early repair response of cartilage defects in trochlea (TR) and medial femoral condyle (MFC) at 2-3 weeks after bone marrow stimulation. DESIGN:Bilateral full-thickness cartilage defects were generated in central trochlear groove and MFC of skeletally mature rabbits. ...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章

    doi:10.1016/j.joca.2013.04.010

    authors: Chen H,Chevrier A,Hoemann CD,Sun J,Lascau-Coman V,Buschmann MD

    更新日期:2013-07-01 00:00:00

  • Radiographic scoring methods in hand osteoarthritis--a systematic literature search and descriptive review.

    abstract:OBJECTIVE:This systematic literature review aimed to evaluate the use of conventional radiography (CR) in hand osteoarthritis (OA) and to assess the metric properties of the different radiographic scoring methods. DESIGN:Medical literature databases up to November 2013 were systematically reviewed for studies reportin...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章,评审

    doi:10.1016/j.joca.2014.05.026

    authors: Visser AW,Bøyesen P,Haugen IK,Schoones JW,van der Heijde DM,Rosendaal FR,Kloppenburg M

    更新日期:2014-10-01 00:00:00

  • Stepwise preconditioning enhances mesenchymal stem cell-based cartilage regeneration through epigenetic modification.

    abstract:OBJECTIVE:This study is to investigate the functions and underlying mechanisms of mesenchymal stem cells (MSCs) underwent stepwise preconditioning in chondrogenic medium before expansion, then further explore their therapeutic effects in a surgically induced osteoarthritis (OA) model. METHODS:MSCs isolated from the ad...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章

    doi:10.1016/j.joca.2017.05.008

    authors: Lin S,Lee WYW,Xu L,Wang Y,Chen Y,Ho KKW,Qin L,Jiang X,Cui L,Li G

    更新日期:2017-09-01 00:00:00

  • Validation of the Dutch version of the Hip disability and Osteoarthritis Outcome Score.

    abstract:INTRODUCTION:The Hip disability and Osteoarthritis Outcome Score (HOOS) was constructed in Sweden; this questionnaire has proved to be valid for persons with hip disability with or without hip osteoarthritis (OA) and with high demands of physical function. OBJECTIVE:The objective of this study was to evaluate the inte...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章

    doi:10.1016/j.joca.2006.06.014

    authors: de Groot IB,Reijman M,Terwee CB,Bierma-Zeinstra SM,Favejee M,Roos EM,Verhaar JA

    更新日期:2007-01-01 00:00:00

  • Depth-dependent compressive properties of normal aged human femoral head articular cartilage: relationship to fixed charge density.

    abstract:OBJECTIVES:Determine the depth-varying confined and osmotic compression moduli of normal human articular cartilage from the femoral head, and test whether these moduli are dependent on fixed charge density. METHODS AND RESULTS:Using an automated instrument to allow epifluorescence microscopy analysis during confined c...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章

    doi:10.1053/joca.2001.0424

    authors: Chen SS,Falcovitz YH,Schneiderman R,Maroudas A,Sah RL

    更新日期:2001-08-01 00:00:00

  • Detection of changes in cartilage water content using MRI T2-mapping in vivo.

    abstract:OBJECTIVES:Osteoarthritis (OA) is the most prevalent chronic disease in the elderly, and it is generally diagnosed at an advanced state when treatment is difficult if not impossible. The early form of OA is characterized by an elevated water content in the cartilage tissue. The purpose of this study was to verify in vi...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章

    doi:10.1053/joca.2002.0847

    authors: Liess C,Lüsse S,Karger N,Heller M,Glüer CC

    更新日期:2002-12-01 00:00:00

  • Effectiveness of splinting for pain and function in people with thumb carpometacarpal osteoarthritis: a systematic review with meta-analysis.

    abstract:OBJECTIVE:To examine the effectiveness of splinting for reducing pain and improving function and health-related quality of life (HR-QoL) in people with thumb carpometacarpal osteoarthritis (CMC OA). DESIGN:The Cochrane Library, MEDLINE, Embase, CINAHL, ISI Web of Science, Scopus and Google Scholar, 3 trial registries ...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章,meta分析

    doi:10.1016/j.joca.2018.09.012

    authors: Buhler M,Chapple CM,Stebbings S,Sangelaji B,Baxter GD

    更新日期:2019-04-01 00:00:00

  • Brace treatment for osteoarthritis of the knee: a prospective randomized multi-centre trial.

    abstract:OBJECTIVE:To evaluate the effect of a brace intended to reduce load in patients with medial or lateral compartmental osteoarthritis (OA) and concurrent varus or valgus alignment, respectively. DESIGN:This multi-centre randomized controlled trial (performed 2001-2003) studies the additive effect of a brace intended to ...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章,多中心研究,随机对照试验

    doi:10.1016/j.joca.2006.02.004

    authors: Brouwer RW,van Raaij TM,Verhaar JA,Coene LN,Bierma-Zeinstra SM

    更新日期:2006-08-01 00:00:00

  • Precision and accuracy of joint space width measurements of the medial compartment of the knee using standardized MTP semi-flexed radiographs.

    abstract:OBJECTIVE:To quantify the precision and accuracy of measurements of joint space width (JSW) and joint space narrowing (JSN) from the medial tibiofemoral compartment of knee radiographs using a simple and easily adaptable protocol. METHODS:Radiographs of a caliper (a surrogate for JSW) were obtained to determine the pr...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章

    doi:10.1016/s1063-4584(03)00158-4

    authors: Dupuis DE,Beynnon BD,Richard MJ,Novotny JE,Skelly JM,Cooper SM

    更新日期:2003-10-01 00:00:00

  • Coexisting lateral tibiofemoral osteoarthritis is associated with worse knee pain in patients with mild medial osteoarthritis.

    abstract:OBJECTIVE:To examine the clinical impact of coexisting lateral osteoarthritis (OA) in knees with mild medial OA. DESIGN:In patients with Kellgren/Lawrence (K/L) grade 2 OA in the medial compartment (n = 100; age: 56-89 years; 80.0% female), anteroposterior knee radiography was used to assess the presence of lateral OA...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章

    doi:10.1016/j.joca.2017.02.801

    authors: Iijima H,Aoyama T,Nishitani K,Ito H,Fukutani N,Isho T,Kaneda E,Kuroki H,Matsuda S

    更新日期:2017-08-01 00:00:00

  • Chondroitin sulfate and/or glucosamine hydrochloride for Kashin-Beck disease: a cluster-randomized, placebo-controlled study.

    abstract:OBJECTIVE:To evaluate the efficacy and safety of chondroitin sulfate and/or glucosamine hydrochloride in alleviating symptoms and improving the dysfunction of Kashin-Beck disease (KBD) patients. METHODS:We undertook a cluster-randomized, placebo-controlled trial in 251 patients with KBD. Participants were randomly all...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章,随机对照试验

    doi:10.1016/j.joca.2012.03.013

    authors: Yue J,Yang M,Yi S,Dong B,Li W,Yang Z,Lu J,Zhang R,Yong J

    更新日期:2012-07-01 00:00:00

  • Estrogen reduces mechanical injury-related cell death and proteoglycan degradation in mature articular cartilage independent of the presence of the superficial zone tissue.

    abstract:OBJECTIVE:To study the effect of 17β-estradiol (E2) and the superficial zone (SFZ) on cell death and proteoglycan degradation in articular cartilage after a single injurious compression in vitro. METHOD:Cartilage explants from the femoropatellar groove of 2 year old cows with or without the SFZ were cultured serum-fre...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章

    doi:10.1016/j.joca.2013.07.007

    authors: Imgenberg J,Rolauffs B,Grodzinsky AJ,Schünke M,Kurz B

    更新日期:2013-11-01 00:00:00

  • Hypoxia, RONS and energy metabolism in articular cartilage.

    abstract:OBJECTIVE:Increased pro-inflammatory cytokines and reactive oxygen and nitrogen species (RONS) occur in osteoarthritis (OA). Oxygen tension can alter the levels of RONS induced by interleukin-1 (IL-1). RONS such as nitric oxide (NO) can alter energy metabolism. The aim of this study was to determine if oxygen tension a...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章

    doi:10.1016/j.joca.2010.06.004

    authors: Fermor B,Gurumurthy A,Diekman BO

    更新日期:2010-09-01 00:00:00

  • Measurement properties of the WOMAC LK 3.1 pain scale.

    abstract:OBJECTIVE:The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) is applied extensively to patients with osteoarthritis of the hip or knee. Previous work has challenged the validity of its physical function scale however an extensive evaluation of its pain scale has not been reported. Our purpose wa...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章

    doi:10.1016/j.joca.2006.09.005

    authors: Stratford PW,Kennedy DM,Woodhouse LJ,Spadoni GF

    更新日期:2007-03-01 00:00:00

  • Psychometric properties of the French translation of the reduced KOOS and HOOS (KOOS-PS and HOOS-PS).

    abstract:OBJECTIVE:To evaluate the psychometric properties of the French KOOS physical function (KOOS-PS) and HOOS physical function (HOOS-PS), specifically its feasibility, reliability, construct validity, and responsiveness. METHODS:Consecutive outpatients consulting for primary knee or hip osteoarthritis (OA) in a rheumatol...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章

    doi:10.1016/j.joca.2009.06.007

    authors: Ornetti P,Perruccio AV,Roos EM,Lohmander LS,Davis AM,Maillefert JF

    更新日期:2009-12-01 00:00:00

  • Assessment of joint space narrowing with conventional standing antero-posterior radiographs: relief in mild-to-moderate pain is not a confounder in recent osteoarthritis structure-modifying drug trials.

    abstract:OBJECTIVE:Knee pain relief has been suggested to potentially alter radioanatomic positioning in conventional standing antero-posterior knee radiographs. This study was performed to determine whether this is always the case and in particular if it applied to two recent randomised, placebo-controlled trials showing both ...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章

    doi:10.1016/j.joca.2006.02.022

    authors: Rovati LC,Pavelka K,Giacovelli G,Reginster JY

    更新日期:2006-01-01 00:00:00

  • Anterior Cruciate Ligament OsteoArthritis Score (ACLOAS): Longitudinal MRI-based whole joint assessment of anterior cruciate ligament injury.

    abstract:OBJECTIVE:To develop a whole joint scoring system, the Anterior Cruciate Ligament OsteoArthritis Score (ACLOAS), for magnetic resonance imaging (MRI)-based assessment of acute anterior cruciate ligament (ACL) injury and follow-up of structural sequelae, and to assess its reliability. DESIGN:Baseline and follow-up 1.5 ...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章,随机对照试验

    doi:10.1016/j.joca.2014.03.006

    authors: Roemer FW,Frobell R,Lohmander LS,Niu J,Guermazi A

    更新日期:2014-05-01 00:00:00

  • Dicam promotes proliferation and maturation of chondrocyte through Indian hedgehog signaling in primary cilia.

    abstract:OBJECTIVES:Primary cilium is required for mechano-biological signal transduction in chondrocytes, and its interaction with extracellular matrix is critical for cartilage homeostasis. However, the role of cilia-associated proteins that affect the function of cilia remains to be elucidated. Here, we show that Dicam has a...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章

    doi:10.1016/j.joca.2018.04.008

    authors: Han S,Park HR,Lee EJ,Jang JA,Han MS,Kim GW,Jeong JH,Choi JY,Beier F,Jung YK

    更新日期:2018-07-01 00:00:00

  • Osteophyte development--molecular characterization of differentiation stages.

    abstract:OBJECTIVE:Osteophytes are non-neoplastic osteo-cartilaginous protrusions growing at the margins of osteoarthritic joints. They can not only be considered as in situ repair tissue, but also represent an excellent in vivo model for induced cartilage repair processes. Our focus was to identify different steps of osteophyt...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章

    doi:10.1053/joca.2002.0873

    authors: Gelse K,Söder S,Eger W,Diemtar T,Aigner T

    更新日期:2003-02-01 00:00:00

  • Human chondrocyte apoptosis in response to mechanical injury.

    abstract:OBJECTIVE:The effect of mechanical injury on chondrocyte viability and matrix degradation was studied. It was proposed that mechanical injury to human cartilage explants results in chondrocyte apoptosis with associated loss of glycosaminoglycans. DESIGN:Full thickness human cartilage explants, 5 mm in diameter were su...

    journal_title:Osteoarthritis and cartilage

    pub_type: 杂志文章

    doi:10.1053/joca.2001.0468

    authors: D'Lima DD,Hashimoto S,Chen PC,Colwell CW Jr,Lotz MK

    更新日期:2001-11-01 00:00:00