The Age-Related Changes in Cartilage and Osteoarthritis

Osteoarthritis (OA) is closely associated with aging, but its underlying mechanism is unclear. Recent publications were reviewed to elucidate the connection between aging and OA. With increasing OA incidence, more senior people are facing heavy financial and social burdens. Age-related OA pathogenesis is not well understood. Recently, it has been realized that age-related changes in other tissues besides articular cartilage may also contribute to OA development. Many factors including senescence-related secretory phenotypes, chondrocytes' low reactivity to growth factors, mitochondrial dysfunction and oxidative stress, and abnormal accumulation of advanced glycation end products (AGEs) may all play key roles in the pathogenesis of age-related OA. Lately, epigenetic regulation of gene expression was recognized for its impact on age-related OA pathogenesis. Up to now, few studies have been reported about the role of miRNA and long-noncoding RNA (lncRNA) in age-related OA. Research focusing on this area may provide valuable insights into OA pathogenesis. OA-induced financial and social burdens have become an increasingly severe threat to older population. Age-related changes in noncartilage tissue should be incorporated in the understanding of OA development. Growing attention on oxidative stress and epigenetics will provide more important clues for the better understanding of the age-related OA.

[1]  J. Sowers,et al.  The role of oxidative stress in the metabolic syndrome. , 2011, Reviews in cardiovascular medicine.

[2]  T. Spector,et al.  A role for PACE4 in osteoarthritis pain: evidence from human genetic association and null mutant phenotype , 2012, Annals of the rheumatic diseases.

[3]  Ying E Zhang,et al.  Non-Smad pathways in TGF-β signaling , 2009, Cell Research.

[4]  J. Bijlsma,et al.  Effect of Collagen Turnover on the Accumulation of Advanced Glycation End Products* , 2000, The Journal of Biological Chemistry.

[5]  J. Buckwalter,et al.  Aging theories of primary osteoarthritis: from epidemiology to molecular biology. , 2004, Rejuvenation research.

[6]  C. Rorabeck,et al.  Damage to type II collagen in aging and osteoarthritis starts at the articular surface, originates around chondrocytes, and extends into the cartilage with progressive degeneration. , 1995, The Journal of clinical investigation.

[7]  David T Felson,et al.  Prevalence of symptomatic hand osteoarthritis and its impact on functional status among the elderly: The Framingham Study. , 2002, American journal of epidemiology.

[8]  Yaobo Xu,et al.  cAMP response element‐binding (CREB) recruitment following a specific CpG demethylation leads to the elevated expression of the matrix metalloproteinase 13 in human articular chondrocytes and osteoarthritis , 2012, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[9]  P. D. Kraan,et al.  A role for age-related changes in TGFβ signaling in aberrant chondrocyte differentiation and osteoarthritis , 2010 .

[10]  R. Schneiderman,et al.  Aggrecan turnover in human articular cartilage: use of aspartic acid racemization as a marker of molecular age. , 1998, Archives of biochemistry and biophysics.

[11]  H. Weinans,et al.  Analysis of osteoarthritis in a mouse model of the progeroid human DNA repair syndrome trichothiodystrophy , 2010, AGE.

[12]  K. Yudoh,et al.  Angiogenic growth factors inhibit chondrocyte ageing in osteoarthritis: potential involvement of catabolic stress‐induced overexpression of caveolin‐1 in cellular ageing , 2009, International journal of rheumatic diseases.

[13]  R. Schneiderman,et al.  Some biochemical and biophysical parameters for the study of the pathogenesis of osteoarthritis: a comparison between the processes of ageing and degeneration in human hip cartilage. , 1989, Connective tissue research.

[14]  L. Peltonen,et al.  PREDISPOSITION TO FAMILIAL OSTEOARTHROSIS LINKED TO TYPE II COLLAGEN GENE , 1989, The Lancet.

[15]  H. Kim,et al.  Animal Model of Osteoarthritis , 2012 .

[16]  T. Kirkwood,et al.  Superoxide dismutase downregulation in osteoarthritis progression and end-stage disease , 2010, Annals of the rheumatic diseases.

[17]  D. Zukor,et al.  Increased type II collagen cleavage by cathepsin K and collagenase activities with aging and osteoarthritis in human articular cartilage , 2012, Arthritis Research & Therapy.

[18]  S. Abramson,et al.  Perturbation of nuclear lamin A causes cell death in chondrocytes. , 2012, Arthritis and rheumatism.

[19]  Thomas Aigner,et al.  Articular cartilage and changes in Arthritis: Cell biology of osteoarthritis , 2001, Arthritis Research & Therapy.

[20]  E. Vitters,et al.  Reduced transforming growth factor-beta signaling in cartilage of old mice: role in impaired repair capacity , 2005, Arthritis research & therapy.

[21]  A. Philip,et al.  ALK1 Opposes ALK5/Smad3 Signaling and Expression of Extracellular Matrix Components in Human Chondrocytes , 2008, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[22]  Goberdhan P Dimri,et al.  Mechanisms of cellular senescence in human and mouse cells , 2004, Biogerontology.

[23]  N. R. Randy Role of growth factors in cartilage repair , 2000 .

[24]  L. Guarente,et al.  Diverse and dynamic functions of the Sir silencing complex , 1999, Nature Genetics.

[25]  T. Kubo,et al.  N‐acetylcysteine prevents nitric oxide‐induced chondrocyte apoptosis and cartilage degeneration in an experimental model of osteoarthritis , 2010, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[26]  Di Chen,et al.  Genetic inhibition of fibroblast growth factor receptor 1 in knee cartilage attenuates the degeneration of articular cartilage in adult mice. , 2012, Arthritis and rheumatism.

[27]  A. Hofman,et al.  Gremlin 1, frizzled-related protein, and Dkk-1 are key regulators of human articular cartilage homeostasis. , 2012, Arthritis and rheumatism.

[28]  J. Buckwalter,et al.  Age‐related decline in chondrocyte response to insulin‐like growth factor‐I: The role of growth factor binding proteins , 1997, Journal of Orthopaedic Research.

[29]  R. Loeser,et al.  Reduction in the chondrocyte response to insulin-like growth factor 1 in aging and osteoarthritis: studies in a non-human primate model of naturally occurring disease. , 2000, Arthritis and rheumatism.

[30]  B. Yoo,et al.  Effects of advanced glycation end products on the expression of COX-2, PGE2 and NO in human osteoarthritic chondrocytes. , 2008, Rheumatology.

[31]  C. Little,et al.  What constitutes an "animal model of osteoarthritis"--the need for consensus? , 2012, Osteoarthritis and cartilage.

[32]  F. Cicuttini,et al.  Association between age and knee structural change: a cross sectional MRI based study , 2005, Annals of the rheumatic diseases.

[33]  Dan Liu,et al.  The telosome/shelterin complex and its functions , 2008, Genome Biology.

[34]  H. Anderson,et al.  Nfat1 regulates adult articular chondrocyte function through its age‐dependent expression mediated by epigenetic histone methylation , 2011, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[35]  A. Cole,et al.  Matrix homeostasis in aging normal human ankle cartilage. , 2002, Arthritis and rheumatism.

[36]  M. Goumans,et al.  Increase in ALK1/ALK5 Ratio as a Cause for Elevated MMP-13 Expression in Osteoarthritis in Humans and Mice1 , 2009, The Journal of Immunology.

[37]  M. Lotz,et al.  Aging-related loss of the chromatin protein HMGB2 in articular cartilage is linked to reduced cellularity and osteoarthritis , 2009, Proceedings of the National Academy of Sciences.

[38]  T. Aigner,et al.  Apoptotic cell death is not a widespread phenomenon in normal aging and osteoarthritis human articular knee cartilage: a study of proliferation, programmed cell death (apoptosis), and viability of chondrocytes in normal and osteoarthritic human knee cartilage. , 2001, Arthritis and rheumatism.

[39]  F. Berenbaum,et al.  Osteoarthritis: an update with relevance for clinical practice , 2011, The Lancet.

[40]  Eun Jin Lee,et al.  Tumor necrosis factor α-mediated cleavage and inactivation of SirT1 in human osteoarthritic chondrocytes. , 2011, Arthritis and rheumatism.

[41]  Tsugio Seki,et al.  Nonoverlapping expression patterns of ALK1 and ALK5 reveal distinct roles of each receptor in vascular development , 2006, Laboratory Investigation.

[42]  W. Rejeski,et al.  Modifiers of change in physical functioning in older adults with knee pain: the Observational Arthritis Study in Seniors (OASIS). , 2001, Arthritis and rheumatism.

[43]  Joseph A. Buckwalter,et al.  The Role of Chondrocyte Senescence in the Pathogenesis of Osteoarthritis and in Limiting Cartilage Repair , 2003, The Journal of bone and joint surgery. American volume.

[44]  T. Aigner,et al.  Apoptosis in osteoarthritis. , 2004, Rheumatic diseases clinics of North America.

[45]  D. D’Lima,et al.  Cell death in cartilage. , 2004, Osteoarthritis and cartilage.

[46]  J. Buckwalter,et al.  Telomere erosion and senescence in human articular cartilage chondrocytes. , 2001, The journals of gerontology. Series A, Biological sciences and medical sciences.

[47]  A. Cerami,et al.  Protein glycation, diabetes, and aging. , 2001, Recent progress in hormone research.

[48]  J. Campisi,et al.  Cellular senescence: when bad things happen to good cells , 2007, Nature Reviews Molecular Cell Biology.

[49]  K. Maiese,et al.  The Wnt signaling pathway: aging gracefully as a protectionist? , 2008, Pharmacology & therapeutics.

[50]  R. Loeser Aging processes and the development of osteoarthritis , 2013, Current opinion in rheumatology.

[51]  Joseph A Buckwalter,et al.  Rotenone prevents impact‐induced chondrocyte death , 2010, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[52]  L. V. van Grunsven,et al.  Advanced glycation end products induce production of reactive oxygen species via the activation of NADPH oxidase in murine hepatic stellate cells. , 2010, Journal of hepatology.

[53]  S. Goldring,et al.  Osteoarthritis: a disease of the joint as an organ. , 2012, Arthritis and rheumatism.

[54]  Albert C. Chen,et al.  Induction of advanced glycation end products and alterations of the tensile properties of articular cartilage. , 2002, Arthritis and rheumatism.

[55]  D. Zukor,et al.  Sites of collagenase cleavage and denaturation of type II collagen in aging and osteoarthritic articular cartilage and their relationship to the distribution of matrix metalloproteinase 1 and matrix metalloproteinase 13. , 2002, Arthritis and rheumatism.

[56]  A. Hofman,et al.  A variant in MCF2L is associated with osteoarthritis. , 2011, American journal of human genetics.

[57]  Wilhelm Palm,et al.  How shelterin protects mammalian telomeres. , 2008, Annual review of genetics.

[58]  R. Loeser,et al.  Age-related changes in the musculoskeletal system and the development of osteoarthritis. , 2010, Clinics in geriatric medicine.

[59]  E. Quenneville,et al.  Defects in articular cartilage metabolism and early arthritis in fibroblast growth factor receptor 3 deficient mice. , 2006, Human molecular genetics.

[60]  H. Sun,et al.  Events in Articular Chondrocytes with Aging , 2011, Current osteoporosis reports.

[61]  A. Augello,et al.  Mesenchymal stem cells from development to postnatal joint homeostasis, aging, and disease. , 2010, Birth defects research. Part C, Embryo today : reviews.

[62]  T. Ochi,et al.  Regional differences in chondrocyte metabolism in osteoarthritis: a detailed analysis by laser capture microdissection. , 2008, Arthritis and rheumatism.

[63]  M. Goumans,et al.  Balancing the activation state of the endothelium via two distinct TGF‐β type I receptors , 2002, The EMBO journal.

[64]  Yuqing Zhang,et al.  Epidemiology of OA , 2013 .

[65]  W. B. van den Berg,et al.  Expression of transforming growth factor-β (TGFβ) and the TGFβ signalling molecule SMAD-2P in spontaneous and instability-induced osteoarthritis: role in cartilage degradation, chondrogenesis and osteophyte formation , 2006, Annals of the rheumatic diseases.

[66]  C. Farquharson,et al.  Cartilage development and degeneration: a Wnt Wnt situation , 2012, Cell biochemistry and function.

[67]  A Shirazi-Adl,et al.  Computational biomechanics of articular cartilage of human knee joint: effect of osteochondral defects. , 2009, Journal of biomechanics.

[68]  F. Dell’Accio,et al.  Identification of the molecular response of articular cartilage to injury, by microarray screening: Wnt-16 expression and signaling after injury and in osteoarthritis. , 2008, Arthritis and rheumatism.

[69]  P. Marie,et al.  Extrinsic mechanisms involved in age-related defective bone formation. , 2011, The Journal of clinical endocrinology and metabolism.

[70]  J. Melendez,et al.  Mitochondrial redox control of matrix metalloproteinases. , 2004, Free radical biology & medicine.

[71]  P. Robbins,et al.  Nitric oxide in osteoarthritis. , 1999, Osteoarthritis and cartilage.

[72]  Alice Maroudas,et al.  Crosslinking by advanced glycation end products increases the stiffness of the collagen network in human articular cartilage: a possible mechanism through which age is a risk factor for osteoarthritis. , 2002, Arthritis and rheumatism.

[73]  C. Sanchez,et al.  Increased apoptotic chondrocytes in articular cartilage from adult heterozygous SirT1 mice , 2012, Annals of the rheumatic diseases.

[74]  S. Chubinskaya,et al.  Age-related changes in cartilage endogenous osteogenic protein-1 (OP-1). , 2002, Biochimica et biophysica acta.

[75]  M. Bayliss,et al.  Sulfation of Chondroitin Sulfate in Human Articular Cartilage , 1999, The Journal of Biological Chemistry.

[76]  M. Hochberg,et al.  Osteoarthritis I: epidemiology. , 1984, Maryland state medical journal.

[77]  W. B. van den Berg,et al.  Loss of transforming growth factor counteraction on interleukin 1 mediated effects in cartilage of old mice , 2002, Annals of the rheumatic diseases.

[78]  R. O’Keefe,et al.  Activation of β‐Catenin Signaling in Articular Chondrocytes Leads to Osteoarthritis‐Like Phenotype in Adult β‐Catenin Conditional Activation Mice , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[79]  M. Tiku,et al.  Evidence Linking Chondrocyte Lipid Peroxidation to Cartilage Matrix Protein Degradation , 2000, The Journal of Biological Chemistry.

[80]  Tashima Ck Letter: Striae gravidarum. , 1974 .

[81]  D. Lawrence Latent-TGF-β: An overview , 2001, Molecular and Cellular Biochemistry.

[82]  A. Hofman,et al.  A functional polymorphism in the catechol-O-methyltransferase gene is associated with osteoarthritis-related pain. , 2009, Arthritis and rheumatism.

[83]  M. Akagi,et al.  Induction of bovine articular chondrocyte senescence with oxidized low-density lipoprotein through lectin-like oxidized low-density lipoprotein receptor 1. , 2009, Arthritis and rheumatism.

[84]  W. B. van den Berg,et al.  A role for age-related changes in TGFβ signaling in aberrant chondrocyte differentiation and osteoarthritis , 2010, Arthritis Research & Therapy.

[85]  S. Gabriel,et al.  Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. , 2008, Arthritis and rheumatism.

[86]  W. Richter,et al.  Regulation of H19 and its encoded microRNA-675 in osteoarthritis and under anabolic and catabolic in vitro conditions , 2012, Journal of Molecular Medicine.

[87]  R. Bank,et al.  Ageing and zonal variation in post-translational modification of collagen in normal human articular cartilage. The age-related increase in non-enzymatic glycation affects biomechanical properties of cartilage. , 1998, The Biochemical journal.

[88]  Gheorghe Luta,et al.  Lifetime risk of symptomatic knee osteoarthritis. , 2008, Arthritis and rheumatism.

[89]  J. Hancock,et al.  Detection of superoxide and NADPH oxidase in porcine articular chondrocytes. , 1997, Free radical biology & medicine.

[90]  C. V. van Blitterswijk,et al.  A Wnt/β-catenin negative feedback loop inhibits interleukin-1-induced matrix metalloproteinase expression in human articular chondrocytes. , 2012, Arthritis and rheumatism.

[91]  Joanne M. Jordan,et al.  Epidemiology of osteoarthritis. , 2008, Rheumatic diseases clinics of North America.

[92]  T. Huizinga,et al.  Determinants of absence of osteoarthritis in old age , 2011, Scandinavian journal of rheumatology.

[93]  J. Buckwalter,et al.  Age‐Related changes in cartilage proteoglycans: Quantitative electron microscopic studies , 1994, Microscopy research and technique.

[94]  F. Blanco,et al.  The role of mitochondria in osteoarthritis , 2011, Nature Reviews Rheumatology.

[95]  D. Hunter,et al.  The epidemiology of osteoarthritis. , 2014, Best practice & research. Clinical rheumatology.

[96]  J. Campisi Senescent Cells, Tumor Suppression, and Organismal Aging: Good Citizens, Bad Neighbors , 2005, Cell.

[97]  G. Striker,et al.  Advanced glycation end products in foods and a practical guide to their reduction in the diet. , 2010, Journal of the American Dietetic Association.

[98]  R. Loeser,et al.  Increased oxidative stress with aging reduces chondrocyte survival: correlation with intracellular glutathione levels. , 2003, Arthritis & Rheumatism.

[99]  C. Sanchez,et al.  Epigenetics, sirtuins and osteoarthritis. , 2012, Joint, bone, spine : revue du rhumatisme.

[100]  F Eckstein,et al.  Age-related changes in the morphology and deformational behavior of knee joint cartilage. , 2001, Arthritis and rheumatism.

[101]  H. Sun Mechanical loading, cartilage degradation, and arthritis , 2010, Annals of the New York Academy of Sciences.

[102]  K. Yudoh,et al.  Potential involvement of oxidative stress in cartilage senescence and development of osteoarthritis: oxidative stress induces chondrocyte telomere instability and downregulation of chondrocyte function , 2005, Arthritis research & therapy.

[103]  D. Kögel,et al.  TGF-β1 activates two distinct type I receptors in neurons , 2005, The Journal of Cell Biology.

[104]  W. Shen,et al.  Advanced glycation end products induce chemokine/cytokine production via activation of p38 pathway and inhibit proliferation and migration of bone marrow mesenchymal stem cells , 2010, Cardiovascular diabetology.

[105]  C. Nüesch,et al.  Aging and Osteoarthritis: An Inevitable Encounter? , 2012, Journal of aging research.

[106]  Habib Messai,et al.  Articular chondrocytes from aging rats respond poorly to insulin-like growth factor-1: an altered signaling pathway , 2000, Mechanisms of Ageing and Development.

[107]  Wan‐Lin Wu,et al.  Advanced glycation end products cause collagen II reduction by activating Janus kinase/signal transducer and activator of transcription 3 pathway in porcine chondrocytes. , 2011, Rheumatology.

[108]  J. Thacker,et al.  The XRCC genes: expanding roles in DNA double-strand break repair. , 2004, DNA repair.

[109]  A. Kozubík,et al.  FGFR3 signaling induces a reversible senescence phenotype in chondrocytes similar to oncogene-induced premature senescence. , 2010, Bone.

[110]  J. Han,et al.  Distinct regulation of gene expression in human endothelial cells by TGF-beta and its receptors. , 2006, Microvascular research.

[111]  M. Bayliss,et al.  Age-related changes in the synthesis of link protein and aggrecan in human articular cartilage: implications for aggregate stability. , 1999, The Biochemical journal.

[112]  A. Brandl,et al.  Oxidative stress induces senescence in chondrocytes , 2011, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[113]  W. B. van den Berg,et al.  Transforming growth factor-beta 1 stimulates articular chondrocyte proteoglycan synthesis and induces osteophyte formation in the murine knee joint. , 1994, Laboratory investigation; a journal of technical methods and pathology.

[114]  T. Brümmendorf,et al.  Replicative aging of human articular chondrocytes during ex vivo expansion. , 2002, Arthritis and rheumatism.

[115]  W. Horton,et al.  Chondrocyte apoptosis in development, aging and disease. , 1998, Matrix biology : journal of the International Society for Matrix Biology.

[116]  Chang-Keun Lee,et al.  Advanced glycation end products increases matrix metalloproteinase‐1, ‐3, and ‐13, and TNF‐α in human osteoarthritic chondrocytes , 2007, FEBS letters.

[117]  S. Froum,et al.  The need for consensus. , 2014, The International journal of periodontics & restorative dentistry.

[118]  Sang-Gu Hwang,et al.  Wnt‐3a regulates chondrocyte differentiation via c‐Jun/AP‐1 pathway , 2005, FEBS letters.

[119]  Jonas Larsson,et al.  Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFbeta/ALK5 signaling. , 2003, Molecular cell.

[120]  B. Johnstone,et al.  Immunohistochemical analysis of 3-B-(-) and 7-D-4 epitope expression in canine osteoarthritis. , 1993, Arthritis and rheumatism.

[121]  Gheorghe Luta,et al.  Prevalence of knee symptoms and radiographic and symptomatic knee osteoarthritis in African Americans and Caucasians: the Johnston County Osteoarthritis Project. , 2007, The Journal of rheumatology.

[122]  W. Horton,et al.  Chondrocyte apoptosis increases with age in the articular cartilage of adult animals , 1998, The Anatomical record.

[123]  Daniel Levy,et al.  Evidence for a Mendelian gene in a segregation analysis of generalized radiographic osteoarthritis: the Framingham Study. , 1998, Arthritis and rheumatism.

[124]  T. Hardingham,et al.  Age-related changes in the content of the C-terminal region of aggrecan in human articular cartilage. , 1996, The Biochemical journal.

[125]  P. Butler,et al.  Vulnerability to ROS-induced cell death in ageing articular cartilage: the role of antioxidant enzyme activity. , 2005, Osteoarthritis and cartilage.

[126]  Jennifer M. Hootman,et al.  Prevalence of doctor-diagnosed arthritis and arthritis-attributable activity limitation --- United States, 2007-2009. , 2010, MMWR. Morbidity and mortality weekly report.

[127]  Marie-José Goumans,et al.  Age-dependent alteration of TGF-β signalling in osteoarthritis , 2011, Cell and Tissue Research.

[128]  M. Akagi,et al.  Induction of hypertrophic chondrocyte-like phenotypes by oxidized LDL in cultured bovine articular chondrocytes through increase in oxidative stress. , 2010, Osteoarthritis and cartilage.

[129]  C. Heldin,et al.  The type I TGF-β receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner , 2008, Nature Cell Biology.

[130]  K. Mikecz,et al.  Fibroblast growth factor receptor 1 is principally responsible for fibroblast growth factor 2-induced catabolic activities in human articular chondrocytes , 2011, Arthritis research & therapy.

[131]  M. Mörgelin,et al.  Age-related changes in the composition, the molecular stoichiometry and the stability of proteoglycan aggregates extracted from human articular cartilage. , 2003, The Biochemical journal.

[132]  Bjarni V. Halldórsson,et al.  Meta-analysis of genome-wide association studies confirms a susceptibility locus for knee osteoarthritis on chromosome 7q22 , 2010, Annals of the rheumatic diseases.

[133]  T. Spector,et al.  The Ile585Val TRPV1 variant is involved in risk of painful knee osteoarthritis , 2011, Annals of the rheumatic diseases.

[134]  W. Yin,et al.  Oxidative Stress Inhibits Insulin-like Growth Factor-I Induction of Chondrocyte Proteoglycan Synthesis through Differential Regulation of Phosphatidylinositol 3-Kinase-Akt and MEK-ERK MAPK Signaling Pathways* , 2009, The Journal of Biological Chemistry.

[135]  S. Binder-Macleod,et al.  Characterization of the human quadriceps muscle in active elders. , 2001, Archives of physical medicine and rehabilitation.

[136]  F. Guilak,et al.  Reactive nitrogen and oxygen species in interleukin-1-mediated DNA damage associated with osteoarthritis. , 2008, Osteoarthritis and cartilage.

[137]  J. Bijlsma,et al.  Age-related decrease in proteoglycan synthesis of human articular chondrocytes: the role of nonenzymatic glycation. , 1999, Arthritis and rheumatism.

[138]  J. Buckwalter,et al.  The impact of osteoarthritis: implications for research. , 2004, Clinical orthopaedics and related research.

[139]  N. Oreiro,et al.  Mitochondrial DNA haplogroups and serum levels of proteolytic enzymes in patients with osteoarthritis , 2010, Annals of the rheumatic diseases.

[140]  C. Helmick,et al.  Prevalence of Hip Symptoms and Radiographic and Symptomatic Hip Osteoarthritis in African Americans and Caucasians: The Johnston County Osteoarthritis Project , 2009, The Journal of Rheumatology.

[141]  Y. Kawakami,et al.  Chromatin protein HMGB2 regulates articular cartilage surface maintenance via β-catenin pathway , 2009, Proceedings of the National Academy of Sciences.

[142]  M. Hochberg,et al.  Defining incident radiographic hip osteoarthritis for epidemiologic studies in women. , 2009, Arthritis and rheumatism.

[143]  S. Park,et al.  Up-regulation of Caveolin Attenuates Epidermal Growth Factor Signaling in Senescent Cells* , 2000, The Journal of Biological Chemistry.

[144]  E. Bradley,et al.  Wnt5b regulates mesenchymal cell aggregation and chondrocyte differentiation through the planar cell polarity pathway , 2011, Journal of cellular physiology.

[145]  P. Guerne,et al.  Growth factor responsiveness of human articular chondrocytes in aging and development. , 1995, Arthritis and rheumatism.

[146]  E. Vignon,et al.  The cell density of human femoral head cartilage. , 1976, Clinical orthopaedics and related research.

[147]  Joseph A. Buckwalter,et al.  Aging, articular cartilage chondrocyte senescence and osteoarthritis , 2004, Biogerontology.

[148]  C. Blitterswijk,et al.  A WNT/β-catenin negative feedback loop inhibits IL-1β induced mmp expression in human articular chondrocytes , 2012 .

[149]  A. Umezawa,et al.  MicroRNA‐199a‐3p, microRNA‐193b, and microRNA‐320c are correlated to aging and regulate human cartilage metabolism , 2012, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[150]  J. Pelletier,et al.  Human osteoarthritic chondrocytes possess an increased number of insulin-like growth factor 1 binding sites but are unresponsive to its stimulation. Possible role of IGF-1-binding proteins. , 1994, Arthritis and rheumatism.

[151]  A. Hofman,et al.  The GDF5 rs143383 polymorphism is associated with osteoarthritis of the knee with genome-wide statistical significance , 2010, Annals of the rheumatic diseases.

[152]  K. Yudoh,et al.  Catabolic stress induces features of chondrocyte senescence through overexpression of caveolin 1: possible involvement of caveolin 1-induced down-regulation of articular chondrocytes in the pathogenesis of osteoarthritis. , 2006, Arthritis and rheumatism.