Cellular senescence in aging and osteoarthritis

Abstract — It is well accepted that age is an important contributing factor to poor cartilage repair following injury, and to the development of osteoarthritis. Cellular senescence, the loss of the ability of cells to divide, has been noted as the major factor contributing to age-related changes in cartilage homeostasis, function, and response to injury. The underlying mechanisms of cellular senescence, while not fully understood, have been associated with telomere erosion, DNA damage, oxidative stress, and inflammation. In this review, we discuss the causes and consequences of cellular senescence, and the associated biological challenges in cartilage repair. In addition, we present novel strategies for modulation of cellular senescence that may help to improve cartilage regeneration in an aging population.

[1]  J. Chan,et al.  Human First‐Trimester Fetal MSC Express Pluripotency Markers and Grow Faster and Have Longer Telomeres Than Adult MSC , 2007, Stem cells.

[2]  M. Pei,et al.  Cell senescence: a challenge in cartilage engineering and regeneration. , 2012, Tissue engineering. Part B, Reviews.

[3]  Chia-Jung Li,et al.  Synergistic Protection of N-Acetylcysteine and Ascorbic Acid 2-Phosphate on Human Mesenchymal Stem cells Against Mitoptosis, Necroptosis and Apoptosis , 2015, Scientific Reports.

[4]  W. Maloney,et al.  Collagen VI enhances cartilage tissue generation by stimulating chondrocyte proliferation. , 2015, Tissue engineering. Part A.

[5]  J. Hui,et al.  Advances in Mesenchymal Stem Cell-based Strategies for Cartilage Repair and Regeneration , 2014, Stem Cell Reviews and Reports.

[6]  Kye-Yong Song,et al.  Effect of ascorbic acid on bone marrow-derived mesenchymal stem cell proliferation and differentiation. , 2008, Journal of bioscience and bioengineering.

[7]  Hagen Schmal,et al.  In vitro cell quality of articular chondrocytes assigned for autologous implantation in dependence of specific patient characteristics , 2011, Archives of Orthopaedic and Trauma Surgery.

[8]  Xinqiao Jia,et al.  Injectable perlecan domain 1-hyaluronan microgels potentiate the cartilage repair effect of BMP2 in a murine model of early osteoarthritis , 2012, Biomedical materials.

[9]  Takako Sasaki,et al.  The major basement membrane components localize to the chondrocyte pericellular matrix--a cartilage basement membrane equivalent? , 2008, Matrix biology : journal of the International Society for Matrix Biology.

[10]  G. Bentley,et al.  Degenerative arthritis after intra-articular fractures of the knee. Long-term results. , 1990, The Journal of bone and joint surgery. British volume.

[11]  S. Lim,et al.  Human Mesenchymal Stem Cell-Derived Exosomes Promote Orderly Cartilage Regeneration in an Immunocompetent Rat Osteochondral Defect Model , 2016 .

[12]  H. Roos,et al.  Osteoarthritis of the knee after injury to the anterior cruciate ligament or meniscus: the influence of time and age. , 1995, Osteoarthritis and cartilage.

[13]  H. Yousef,et al.  Embryonic anti-aging niche , 2011, Aging.

[14]  M. Pei,et al.  Extracellular matrix deposited by synovium‐derived stem cells delays replicative senescent chondrocyte dedifferentiation and enhances redifferentiation , 2012, Journal of cellular physiology.

[15]  B. Swoboda,et al.  Matrilin-3 in human articular cartilage: increased expression in osteoarthritis. , 2002, Osteoarthritis and cartilage.

[16]  Seon-Mi Yu,et al.  Thymoquinone-induced reactive oxygen species causes apoptosis of chondrocytes via PI3K/Akt and p38kinase pathway , 2013, Experimental biology and medicine.

[17]  J. Hui,et al.  A comparison between the chondrogenic potential of human bone marrow stem cells (BMSCs) and adipose-derived stem cells (ADSCs) taken from the same donors. , 2007, Tissue engineering.

[18]  Jinwu Peng,et al.  Matrilin-2 Is a Widely Distributed Extracellular Matrix Protein and a Potential Biomarker in the Early Stage of Osteoarthritis in Articular Cartilage , 2014, BioMed research international.

[19]  M. Pei,et al.  Extracellular matrix enhances differentiation of adipose stem cells from infrapatellar fat pad toward chondrogenesis , 2013, Journal of tissue engineering and regenerative medicine.

[20]  Wei Wang,et al.  An anti-inflammatory cell-free collagen/resveratrol scaffold for repairing osteochondral defects in rabbits. , 2014, Acta biomaterialia.

[21]  S. Lou,et al.  Recovery of function in osteoarthritic chondrocytes induced by p16INK4a-specific siRNA in vitro. , 2004, Rheumatology.

[22]  Chia‐cheng Chang,et al.  Accelerated growth and prolonged lifespan of adipose tissue-derived human mesenchymal stem cells in a medium using reduced calcium and antioxidants. , 2005, Stem cells and development.

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

[24]  C. Chiu,et al.  Hypoxia inhibits senescence and maintains mesenchymal stem cell properties through down-regulation of E2A-p21 by HIF-TWIST. , 2011, Blood.

[25]  A. Dopazo,et al.  Human mesenchymal stem cell-replicative senescence and oxidative stress are closely linked to aneuploidy , 2013, Cell Death and Disease.

[26]  T. Guggi,et al.  Marrow stimulation techniques. , 2008, Injury.

[27]  I. Bellantuono,et al.  Study of Telomere Length Reveals Rapid Aging of Human Marrow Stromal Cells following In Vitro Expansion , 2004, Stem cells.

[28]  Yue Zhao,et al.  Protective Effect of Resveratrol against IL-1β-Induced Inflammatory Response on Human Osteoarthritic Chondrocytes Partly via the TLR4/MyD88/NF-κB Signaling Pathway: An “in Vitro Study” , 2014, International journal of molecular sciences.

[29]  T. Aigner,et al.  Ultrastructural localization of type VI collagen in normal adult and osteoarthritic human articular cartilage. , 2002, Osteoarthritis and cartilage.

[30]  C. Yeow,et al.  Temporal activation of β-catenin signaling in the chondrogenic process of mesenchymal stem cells affects the phenotype of the cartilage generated. , 2012, Stem cells and development.

[31]  Ivan Martin,et al.  Age related changes in human articular chondrocyte yield, proliferation and post-expansion chondrogenic capacity. , 2004, Osteoarthritis and cartilage.

[32]  L. Chin,et al.  Telomere dysfunction induces metabolic and mitochondrial compromise , 2011, Nature.

[33]  D. Harris,et al.  Donor age negatively impacts adipose tissue-derived mesenchymal stem cell expansion and differentiation , 2014, Journal of Translational Medicine.

[34]  Jane Ru Choi,et al.  Impact of low oxygen tension on stemness, proliferation and differentiation potential of human adipose-derived stem cells. , 2014, Biochemical and biophysical research communications.

[35]  Andrew M. Handorf,et al.  Induction of Mesenchymal Stem Cell Chondrogenesis Through Sequential Administration of Growth Factors Within Specific Temporal Windows , 2014, Journal of cellular physiology.

[36]  Young-ho Kim Mesenchymal stem cells cultured under hypoxia escape from senescence via down-regulation of p16 and extracellular signal regulated kinase , 2010 .

[37]  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.

[38]  S. Lim,et al.  Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration. , 2016, Osteoarthritis and cartilage.

[39]  J. Campisi,et al.  p38MAPK is a novel DNA damage response‐independent regulator of the senescence‐associated secretory phenotype , 2011, The EMBO journal.

[40]  Wan-Ju Li,et al.  Macrophage migration inhibitory factor regulates AKT signaling in hypoxic culture to modulate senescence of human mesenchymal stem cells. , 2014, Stem cells and development.

[41]  H. Saya,et al.  Mitogenic signalling and the p16INK4a–Rb pathway cooperate to enforce irreversible cellular senescence , 2006, Nature Cell Biology.

[42]  N. LeBrasseur,et al.  Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders , 2011, Nature.

[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. Spector,et al.  Interleukin-6 is a significant predictor of radiographic knee osteoarthritis: The Chingford study , 2009, Arthritis and rheumatism.

[45]  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.

[46]  T. Spector,et al.  Low-level increases in serum C-reactive protein are present in early osteoarthritis of the knee and predict progressive disease. , 1997, Arthritis and rheumatism.

[47]  M. Kurosaka,et al.  Oxidative stress‐induced apoptosis and matrix loss of chondrocytes is inhibited by eicosapentaenoic acid , 2015, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[48]  B. Olsen,et al.  Exploiting Stem Cell-Extracellular Matrix Interactions for Cartilage Regeneration: A Focus on Basement Membrane Molecules. , 2016, Current stem cell research & therapy.

[49]  B. Min,et al.  Fetal Cartilage-Derived Cells Have Stem Cell Properties and Are a Highly Potent Cell Source for Cartilage Regeneration , 2016, Cell transplantation.

[50]  H. Satoh,et al.  Isolation and characterization of mesenchymal stem cells from human umbilical cord blood: Reevaluation of critical factors for successful isolation and high ability to proliferate and differentiate to chondrocytes as compared to mesenchymal stem cells from bone marrow and adipose tissue , 2011, Journal of cellular biochemistry.

[51]  B. Lim,et al.  Effects of ectopic Nanog and Oct4 overexpression on mesenchymal stem cells. , 2009, Stem cells and development.

[52]  M. Longaker,et al.  In vitro expansion of adipose-derived adult stromal cells in hypoxia enhances early chondrogenesis. , 2007, Tissue engineering.

[53]  T. Aigner,et al.  DNA damage, discoordinated gene expression and cellular senescence in osteoarthritic chondrocytes. , 2012, Osteoarthritis and cartilage.

[54]  TsaiTsung-Lin,et al.  Macrophage migration inhibitory factor regulates AKT signaling in hypoxic culture to modulate senescence of human mesenchymal stem cells. , 2014 .

[55]  Xian Jun Loh,et al.  Advances in hydrogel delivery systems for tissue regeneration. , 2014, Materials science & engineering. C, Materials for biological applications.

[56]  C. Yeow,et al.  Cartilage repair using hyaluronan hydrogel-encapsulated human embryonic stem cell-derived chondrogenic cells. , 2010, Biomaterials.

[57]  T. Brümmendorf,et al.  Telomere length and telomerase activity during expansion and differentiation of human mesenchymal stem cells and chondrocytes , 2003, Journal of Molecular Medicine.

[58]  Nadr M Jomha,et al.  Hypoxia mediated isolation and expansion enhances the chondrogenic capacity of bone marrow mesenchymal stromal cells , 2012, Stem Cell Research & Therapy.

[59]  J. Campisi,et al.  Inflammatory networks during cellular senescence: causes and consequences. , 2010, Trends in molecular medicine.

[60]  Wuyin Li,et al.  Intra‐articular resveratrol injection prevents osteoarthritis progression in a mouse model by activating SIRT1 and thereby silencing HIF‐2α , 2015, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[61]  A. Brandl,et al.  Oxidative stress induces senescence in human mesenchymal stem cells. , 2011, Experimental cell research.

[62]  C. Franceschi,et al.  Inflamm‐aging: An Evolutionary Perspective on Immunosenescence , 2000 .

[63]  M. Marcacci,et al.  Multiple osteochondral arthroscopic grafting (mosaicplasty) for cartilage defects of the knee: prospective study results at 2-year follow-up. , 2005, Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association.

[64]  S E Honkonen,et al.  Degenerative Arthritis After Tibial Plateau Fractures , 1995, Journal of orthopaedic trauma.

[65]  A. Nagy,et al.  Antisenescence effect of mouse embryonic stem cell conditioned medium through a PDGF/FGF pathway , 2016, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[66]  B. Moed,et al.  The protective role of the pericellular matrix in chondrocyte apoptosis. , 2009, Tissue engineering. Part A.

[67]  N. Miosge,et al.  Nidogen-1 and nidogen-2 in healthy human cartilage and in late-stage osteoarthritis cartilage. , 2008, Arthritis and rheumatism.

[68]  S. Roberts,et al.  Bone marrow-derived mesenchymal stem cells become antiangiogenic when chondrogenically or osteogenically differentiated: implications for bone and cartilage tissue engineering. , 2014, Tissue engineering. Part A.

[69]  G. Bentley,et al.  Who is the ideal candidate for autologous chondrocyte implantation? , 2006, The Journal of bone and joint surgery. British volume.

[70]  D. Covas,et al.  Mechanisms involved in the therapeutic properties of mesenchymal stem cells. , 2009, Cytokine & growth factor reviews.

[71]  Joseph A Buckwalter,et al.  Oxygen effects on senescence in chondrocytes and mesenchymal stem cells: consequences for tissue engineering. , 2004, The Iowa orthopaedic journal.

[72]  A. Hess,et al.  Paracrine effect of transplanted rib chondrocyte spheroids supports formation of secondary cartilage repair tissue , 2009, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[73]  Joseph A Buckwalter,et al.  The Potential of Human Allogeneic Juvenile Chondrocytes for Restoration of Articular Cartilage , 2010, The American journal of sports medicine.

[74]  A. Cole,et al.  Increased matrix metalloproteinase-13 production with aging by human articular chondrocytes in response to catabolic stimuli. , 2005, The journals of gerontology. Series A, Biological sciences and medical sciences.

[75]  C. Bünger,et al.  Combined 3D and hypoxic culture improves cartilage-specific gene expression in human chondrocytes , 2011, Acta orthopaedica.

[76]  J. Buckwalter,et al.  Effects of oxidative damage and telomerase activity on human articular cartilage chondrocyte senescence. , 2004, The journals of gerontology. Series A, Biological sciences and medical sciences.

[77]  L. Hayflick,et al.  The serial cultivation of human diploid cell strains. , 1961, Experimental cell research.

[78]  Clemens A van Blitterswijk,et al.  Trophic effects of mesenchymal stem cells increase chondrocyte proliferation and matrix formation. , 2011, Tissue engineering. Part A.

[79]  S. Abramson,et al.  The antioxidant resveratrol protects against chondrocyte apoptosis via effects on mitochondrial polarization and ATP production. , 2008, Arthritis and rheumatism.

[80]  J. Chang,et al.  Molecular Sciences Comparative Analysis of Human Mesenchymal Stem Cells from Bone Marrow, Adipose Tissue, and Umbilical Cord Blood as Sources of Cell Therapy , 2022 .

[81]  C. Ohlsson,et al.  Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. , 1994, The New England journal of medicine.

[82]  Y. Koh,et al.  Mesenchymal Stem Cell Implantation in Knee Osteoarthritis , 2015, The American journal of sports medicine.

[83]  E. Jones,et al.  Age-related changes in human bone marrow-derived mesenchymal stem cells: Consequences for cell therapies , 2008, Mechanisms of Ageing and Development.

[84]  V. Zachar,et al.  Hypoxia enhances chondrogenic differentiation of human adipose tissue-derived stromal cells in scaffold-free and scaffold systems , 2013, Cell and Tissue Research.

[85]  J. Campisi Cellular senescence: putting the paradoxes in perspective. , 2011, Current opinion in genetics & development.

[86]  R. Loeser,et al.  Aging-related inflammation in osteoarthritis. , 2015, Osteoarthritis and cartilage.

[87]  M. Spector,et al.  Collagen Type IV and Laminin Expressions during Cartilage Repair and in Late Clinically Failed Repair Tissues from Human Subjects , 2016, Cartilage.

[88]  Byung‐Hyun Cha,et al.  Regulation of senescence associated signaling mechanisms in chondrocytes for cartilage tissue regeneration. , 2016, Osteoarthritis and cartilage.

[89]  B. Olsen,et al.  Distribution of Basement Membrane Molecules, Laminin and Collagen Type IV, in Normal and Degenerated Cartilage Tissues , 2014, Cartilage.

[90]  Joel S Greenberger,et al.  Age‐related intrinsic changes in human bone‐marrow‐derived mesenchymal stem cells and their differentiation to osteoblasts , 2008, Aging cell.

[91]  R. Loeser Aging and osteoarthritis: the role of chondrocyte senescence and aging changes in the cartilage matrix. , 2009, Osteoarthritis and cartilage.

[92]  Paula T Hammond,et al.  Enhanced ex vivo expansion of adult mesenchymal stem cells by fetal mesenchymal stem cell ECM. , 2014, Biomaterials.

[93]  Jizong Gao,et al.  Enhanced Tissue Regeneration Potential of Juvenile Articular Cartilage , 2013, The American journal of sports medicine.

[94]  R. Loeser,et al.  AGING AND OSTEOARTHRITIS , 1957, Current opinion in rheumatology.

[95]  E. Pei,et al.  Autologous Bone Marrow–Derived Mesenchymal Stem Cells Versus Autologous Chondrocyte Implantation An Observational Cohort Study , 2010 .

[96]  J. Piette,et al.  p16INK4a and its regulator miR-24 link senescence and chondrocyte terminal differentiation-associated matrix remodeling in osteoarthritis , 2014, Arthritis Research & Therapy.

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

[98]  A. Salminen,et al.  Emerging role of NF-κB signaling in the induction of senescence-associated secretory phenotype (SASP). , 2012, Cellular signalling.

[99]  M. Goldring,et al.  Laminins and Nidogens in the Pericellular Matrix of Chondrocytes: Their Role in Osteoarthritis and Chondrogenic Differentiation. , 2016, The American journal of pathology.

[100]  J. Delaissé,et al.  The distribution pattern of critically short telomeres in human osteoarthritic knees , 2012, Arthritis Research & Therapy.

[101]  M. Chou,et al.  Concurrent Expression of Oct4 and Nanog Maintains Mesenchymal Stem-Like Property of Human Dental Pulp Cells , 2014, International journal of molecular sciences.

[102]  W. B. van den Berg,et al.  TGF-beta signaling in chondrocyte terminal differentiation and osteoarthritis: modulation and integration of signaling pathways through receptor-Smads. , 2009, Osteoarthritis and cartilage.

[103]  R. Loeser,et al.  Human articular chondrocytes produce IL-7 and respond to IL-7 with increased production of matrix metalloproteinase-13 , 2008, Arthritis research & therapy.

[104]  W. Yin,et al.  Aging and Oxidative Stress Reduce the Response of Human Articular Chondrocytes to Insulin‐like Growth Factor 1 and Osteogenic Protein 1 , 2014, Arthritis & rheumatology.

[105]  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.

[106]  J. Buckwalter,et al.  Post-traumatic osteoarthritis: the role of accelerated chondrocyte senescence. , 2004, Biorheology.

[107]  B. Olsen,et al.  Basement membrane molecule expression attendant to chondrogenesis by nucleus pulposus cells and mesenchymal stem cells , 2013, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.