Amelioration of experimental tendinopathy by lentiviral CD44 gene therapy targeting senescence-associated secretory phenotypes

Abstract

CD44 exerts anti-senescence effects in many disease models. We examined senescence in tendinopathy and the effect of CD44 on senescence-associated secretory phenotypes (SASPs). Senescent markers were determined in human tendinopathic long head of bicep (LHB) and normal hamstring tendons. CD44 gene transfer in rat tendinopathic tenocytes stimulated with interleukin (IL)-1β and a rat Achilles tendinopathy model were performed using lentiviral vectors. Expression levels of p53, p21, and p16 and senescence-associated β-galactosidase (SA-β-gal) activity were positively correlated with the severity of human tendinopathy and were higher in rat and human tendinopathic tenocytes than in normal controls. CD44 overexpressed tenocyte transfectants exhibited reduced levels of IL-6, matrix metalloproteinases (MMPs), cyclooxygenase (COX)-2, p53, p21, p16, SA-β-gal, and phospho-nuclear factor (NF)-κB, whereas their collagen type I alpha 1 (COL1A1) and tenomodulin (tnmd) levels were increased when compared with control transfectants under IL-1β-stimulated conditions. In the animal model, CD44 overexpression lowered the ultrasound and histology scores and expression levels of the senescent and SASP markers COX-2 and phospho-NF-κB. Bromodeoxyuridine (BrdU)- and tnmd-positive cell numbers were increased in the LVCD44-transduced tendinopathic tendons. Senescence is positively correlated with tendinopathic severity, and CD44 overexpression may protect the tendinopathic tendons from SASPs via anti-inflammation and maintenance of extracellular matrix homeostasis. CD44 exerts anti-senescence effects in many disease models. We examined senescence in tendinopathy and the effect of CD44 on senescence-associated secretory phenotypes (SASPs). Senescent markers were determined in human tendinopathic long head of bicep (LHB) and normal hamstring tendons. CD44 gene transfer in rat tendinopathic tenocytes stimulated with interleukin (IL)-1β and a rat Achilles tendinopathy model were performed using lentiviral vectors. Expression levels of p53, p21, and p16 and senescence-associated β-galactosidase (SA-β-gal) activity were positively correlated with the severity of human tendinopathy and were higher in rat and human tendinopathic tenocytes than in normal controls. CD44 overexpressed tenocyte transfectants exhibited reduced levels of IL-6, matrix metalloproteinases (MMPs), cyclooxygenase (COX)-2, p53, p21, p16, SA-β-gal, and phospho-nuclear factor (NF)-κB, whereas their collagen type I alpha 1 (COL1A1) and tenomodulin (tnmd) levels were increased when compared with control transfectants under IL-1β-stimulated conditions. In the animal model, CD44 overexpression lowered the ultrasound and histology scores and expression levels of the senescent and SASP markers COX-2 and phospho-NF-κB. Bromodeoxyuridine (BrdU)- and tnmd-positive cell numbers were increased in the LVCD44-transduced tendinopathic tendons. Senescence is positively correlated with tendinopathic severity, and CD44 overexpression may protect the tendinopathic tendons from SASPs via anti-inflammation and maintenance of extracellular matrix homeostasis. IntroductionThe exact pathophysiology of tendinopathy remains unclear and has been attributed to multiple factors, including mechanical overuse,1Cook J.L. Purdam C.R. Is tendon pathology a continuum? A pathology model to explain the clinical presentation of load-induced tendinopathy.Br. J. Sports Med. 2009; 43: 409-416Crossref PubMed Scopus (612) Google Scholar chronic inflammation,2Dakin S.G. Newton J. Martinez F.O. Hedley R. Gwilym S. Jones N. Reid H.A.B. Wood S. Wells G. Appleton L. et al.Chronic inflammation is a feature of Achilles tendinopathy and rupture.Br. J. Sports Med. 2018; 52: 359-367Crossref PubMed Scopus (88) Google Scholar and aging.3Lui P.P.Y. Wong C.M. Biology of tendon stem cells and tendon in aging.Front. Genet. 2020; 10Crossref PubMed Scopus (12) Google Scholar Cell senescence is an irreversible process in which cell-cycle arrest is attributed to the activation of p16INK4a or p53/p21cip stress-responsive signaling pathways.4Campisi J. d'Adda di Fagagna F. Cellular senescence: when bad things happen to good cells.Nat. Rev. Mol. Cell Biol. 2007; 8: 729-740Crossref PubMed Scopus (2911) Google Scholar Senescent cells have particular characteristics, such as excess secretion of matrix-degrading enzymes and pro-inflammatory cytokines,5Hampel B. Fortschegger K. Ressler S. Chang M.W. Unterluggauer H. Breitwieser A. Sommergruber W. Fitzky B. Lepperdinger G. Jansen-Durr P. et al.Increased expression of extracellular proteins as a hallmark of human endothelial cell in vitro senescence.Exp. Gerontol. 2006; 41: 474-481Crossref PubMed Scopus (60) Google Scholar,6Millis A.J. Hoyle M. McCue H.M. Martini H. Differential expression of metalloproteinase and tissue inhibitor of metalloproteinase genes in aged human fibroblasts.Exp. Cell Res. 1992; 201: 373-379Crossref PubMed Scopus (221) Google Scholar designated senescence-associated secretory phenotypes (SASPs)4Campisi J. d'Adda di Fagagna F. Cellular senescence: when bad things happen to good cells.Nat. Rev. Mol. Cell Biol. 2007; 8: 729-740Crossref PubMed Scopus (2911) Google Scholar and expression of lysosomal senescence-associated β-galactosidase (SA-β-gal).7Lee B.Y. Han J.A. Im J.S. Morrone A. Johung K. Goodwin E.C. Kleijer W.J. DiMaio D. Hwang E.S. Senescence-associated beta-galactosidase is lysosomal beta-galactosidase.Aging Cell. 2006; 5: 187-195Crossref PubMed Scopus (722) Google Scholar Interestingly, many of these SASP cytokines and enzymes, including interleukin (IL)-6 and matrix metalloproteinase (MMP)-1 and -3, are implicated in the pathogenesis of tendinopathy.8Abate M. Silbernagel K.G. Siljeholm C. Di Iorio A. De Amicis D. Salini V. Werner R. Paganelli R. Pathogenesis of tendinopathies: inflammation or degeneration?.Arthritis Res. Ther. 2009; 11: 235Crossref PubMed Scopus (309) Google Scholar,9Wang Y. Tang H. He G. Shi Y. Kang X. Lyu J. Zhou M. Zhu M. Zhang J. Tang K. High concentration of aspirin induces apoptosis in rat tendon stem cells via inhibition of the Wnt/β-catenin pathway.Cell. Physiol. Biochem. 2018; 50: 2046-2059Crossref PubMed Scopus (18) Google Scholar IL-1β, one of the main initiators of tendinopathy, induces IL-6, IL-1β, cyclooxygenase (COX)-2, and MMP-1, -3, and -13 gene expression in human tendon cells and reduces the expression levels of tenomodulin (tnmd) and type 1 and 3 collagen in injured tendon-derived cells.10Tsuzaki M. Guyton G. Garrett W. Archambault J. Herzog W. Almekinders L. Bynum D. Yang X. Banes A.J. IL-1β induces COX2, MMP-1,-3 and-13, ADAMTS-4, IL-1β and IL-6 in human tendon cells.J. Orthop. Res. 2003; 21: 256-264Crossref PubMed Scopus (304) Google Scholar,11Zhang K. Asai S. Yu B. Enomoto-Iwamoto M. IL-1β irreversibly inhibits tenogenic differentiation and alters metabolism in injured tendon-derived progenitor cells in vitro.Biochem. Biophys. Res. Commun. 2015; 463: 667-672Crossref PubMed Scopus (45) Google Scholar Furthermore, IL-1β and dexamethasone, two factors that contribute to tendinopathy, have been shown to increase human tenocyte senescence, either alone or in combination.12Jo C.H. Lee S.Y. Yoon K.S. Shin S. Effects of platelet-rich plasma with concomitant use of a corticosteroid on tenocytes from degenerative rotator cuff tears in interleukin 1beta-induced tendinopathic conditions.Am. J. Sports Med. 2017; 45: 1141-1150Crossref PubMed Scopus (35) Google Scholar Therefore, our first hypothesis that senescence is positively correlated with the of is a which is the of of extracellular matrix M. K. K. Y. to inflammation and Google Scholar the and cell senescence in tendinopathy CD44 signaling have been shown to and and differentiation in aged CD44 signaling and J. PubMed Scopus Google Scholar A that anti-senescence CD44 in human cell M. cell to senescence and PubMed Scopus Google Scholar that CD44 of and expression in IL-1β-stimulated tenocytes and that inhibition of the CD44 using an pro-inflammatory and expression in rat tendinopathic J.L. C.H. S.Y. of CD44 induces and matrix metalloproteinase expression in Biol. PubMed Scopus (12) Google S.Y. matrix expression via CD44 in 2017; Google Scholar Therefore, our hypothesis that CD44 tenocytes from cell senescence under tendinopathic were to the to senescence in tendinopathy and to the of CD44 in SASPs in tendinopathy models. A gene CD44 overexpression that senescence positively correlated with the severity of tendinopathy, and CD44 overexpression protect tendinopathic tendons from SASPs in with anti-inflammation and maintenance of senescence in human that CD44 expression positively correlated with the of J.L. C.H. S.Y. of CD44 induces and matrix metalloproteinase expression in Biol. PubMed Scopus (12) Google Scholar the of senescence and a with CD44 disease activity and as as senescent markers in normal and of the and tendinopathic long head of bicep (LHB) tendons and in the hamstring normal and the in to tendinopathy Senescent phenotypes were in the tendinopathic tendon compared with the normal expression of senescent including p53, p21, p16, and SA-β-gal, correlated with tendinopathy severity Furthermore, higher activity in tendinopathic tendons than in normal hamstring tendons senescence in human and rat tendinopathic tendinopathic tenocytes were from Achilles tendons with 1 as J.L. C.H. S.Y. of CD44 induces and matrix metalloproteinase expression in Biol. PubMed Scopus (12) Google Scholar tenocytes were from normal hamstring and tendinopathic tendons. In human cells and the expression of p53, p16, and were higher than in normal hamstring tendons J.L. C.H. S.Y. of CD44 induces and matrix metalloproteinase expression in Biol. PubMed Scopus (12) Google Scholar a cell model in which tenocytes were from Achilles tendons of and or with an of I 1 In cells and the expression of p53, p16, and were higher than in control as determined and and levels of p53, p16, and activity in rat were from the Achilles tendons of or with of I 1 tenocytes were to activity in cells were and Expression levels of p53, p21, and p16 were determined via Expression levels of and p16 were determined via are as the were using the are of two of CD44 lentiviral in vitro reduces the SASPs in rat tendinopathic tendinopathic tenocytes were with lentiviral CD44 to in transfectants in which CD44 overexpressed levels of p53, p21, p16, and -3, and whereas their collagen type I alpha 1 (COL1A1) and levels were increased when compared with control transfectants under IL-1β-stimulated as determined Furthermore, levels of IL-6, MMP-1, and COX-2 were whereas and levels were in LVCD44-transduced tenocyte transfectants than in their in to IL-1β levels of IL-6 in the of LVCD44-transduced tenocyte transfectants were than in control transfectants Furthermore, these transfectants exhibited reduced activity in to IL-1β levels of matrix enzymes, extracellular matrix and senescent markers in LVCD44-transduced rat matrix (MMP)-1 and -3, phospho-nuclear collagen type I alpha 1 tenomodulin p53, p21, and p16 expression levels in control and LVCD44-transduced and tenocytes were stimulated with IL-1β or which stimulated and to IL-6 levels tenocytes were to activity and in to the of cells to cells to IL-6, MMP-1, and expression and tenocytes were stimulated with IL-1β or are of in are as the were using of multiple of CD44 lentiviral in reduces the SASPs and clinical in a rat tendinopathy the in the animal We that CD44 levels were overexpressed in the rat Achilles tendons compared with expression of CD44 in the tendons compared with their Therefore, were in our animal of tendinopathy, including and were in the and the tendinopathic tendons scores ultrasound including and than the control tendons tendons scores than their the of tendinopathy with senescence, and cell and the markers in 3 were and expression and cells were in tendinopathic tendons in levels of and -3, IL-6, SA-β-gal, p53, and were in the than in the the of is as Lee et B.Y. Han J.A. Im J.S. Morrone A. Johung K. Goodwin E.C. Kleijer W.J. DiMaio D. Hwang E.S. Senescence-associated beta-galactosidase is lysosomal beta-galactosidase.Aging Cell. 2006; 5: 187-195Crossref PubMed Scopus (722) Google Scholar expression higher in the than in the control p16 expression the two these that CD44 a in tendinopathy senescence, and of of in rat tendons via of the animal rat Achilles of or lentiviral their Achilles tendons in a were to the the ultrasound and were and CD44 expression levels in the rat Achilles tendon of and as determined via are of two of CD44 overexpression in the rat Achilles tendinopathy the the of or a ultrasound scores of and in and were and of are as the and and the of and tendinopathic shown to and are of the are as the and -3, IL-6, p53, p21, and p16 expression levels in and tendinopathic tendons are of were using the that senescence positively correlated with the severity of tendinopathy in human tendons and in rat and human tendinopathic tenocytes than in controls. CD44 overexpression a gene transfer a effect on rat tendinopathic of CD44 in including p53, p21, p16, SA-β-gal, and IL-6, were in IL-1β-stimulated tenocytes and rat tendinopathic tendons CD44 gene and cell and and -3, and were in the model of CD44 gene in vitro CD44 gene transfer lentiviral in IL-1β-stimulated tendinopathic tenocytes in CD44 overexpression that the including the of activation and gene expression levels of senescence markers p21, and and SASPs and and whereas the expression levels of tendon and were increased under the IL-1β-stimulated In gene via of in rat tendinopathic tendons reduced the ultrasound and scores as as senescence and SASPs and tendon cell in senescent tendon-derived stem cells has been Wong of tendon-derived stem cells from a animal model of Cell. PubMed Scopus Google L. M. et cell and Cell. PubMed Scopus Google Scholar from rat tendons have and higher senescence compared with from which contribute to and tendon Wong of tendon-derived stem cells from a animal model of Cell. PubMed Scopus Google Scholar We correlated these with our that cells in the a higher of senescent markers in the tendinopathic tendons and and that the tenocytes a higher cell and expression levels of p53, p16, and than the tenocytes In aged rat the expression of tendon markers whereas differentiation and CD44 expression were L. M. et cell and Cell. PubMed Scopus Google Scholar a of CD44 in the of cell the their cell or Wong of tendon-derived stem cells from a animal model of Cell. PubMed Scopus Google L. M. et cell and Cell. PubMed Scopus Google Scholar and that lentiviral of CD44 senescence in that cell tenocyte differentiation in with from a tendinopathic Interestingly, increased CD44 expression levels were positively correlated with the of tendinopathy, whereas including IL-6 and and -3, increased in tenocytes CD44 as shown in our J.L. C.H. S.Y. of CD44 induces and matrix metalloproteinase expression in Biol. PubMed Scopus (12) Google Scholar Furthermore, senescence and reduced and Achilles tendon K. M. D. C. X. J. R. et with of Achilles PubMed Scopus Google P. S. C. C. M. D. of tenomodulin in reduced and senescence of tendon Cell. 2015; PubMed Scopus Google Scholar the that CD44 protect tendinopathic tendons from senescence and their disease activity as in our 3 and is a of cell senescence the which in pro-inflammatory SASPs in that cytokines IL-6 and G. J. senescent effect is 2018; PubMed Scopus Google Scholar senescence in cells the signaling and and as as increase H. D. A. G. A. F. M. an in senescence, gene and inhibition of in J. Physiol. Cell Physiol. PubMed Scopus Google Scholar COX-2 activity a inhibitor in senescent an S. D. F. S. K. C. F. C. or senescence COX-2 Cell Res. 2007; PubMed Scopus Google Scholar In aged gene expression is N. G. M. M. K. P. with type I collagen expression a of the in human PubMed Scopus Google Scholar to our IL-1β the expression of matrix-degrading enzymes and IL-6, and and senescent markers p21, and and these effects were in LVCD44-transduced tendinopathic tenocytes In tenocytes in which CD44 overexpressed higher expression of than the control cells in to IL-1β that the CD44 signaling cell senescence is to tendon pathogenesis of tendinopathy in many including IL-1β a disease that induces the expression of matrix-degrading enzymes and reduces M. Guyton G. Garrett W. Archambault J. Herzog W. Almekinders L. Bynum D. Yang X. Banes A.J. IL-1β induces COX2, MMP-1,-3 and-13, ADAMTS-4, IL-1β and IL-6 in human tendon cells.J. Orthop. Res. 2003; 21: 256-264Crossref PubMed Scopus (304) Google Scholar,11Zhang K. Asai S. Yu B. Enomoto-Iwamoto M. IL-1β irreversibly inhibits tenogenic differentiation and alters metabolism in injured tendon-derived progenitor cells in vitro.Biochem. Biophys. Res. Commun. 2015; 463: 667-672Crossref PubMed Scopus (45) Google Scholar from increased J.S. C. C. of senescence in Cell. PubMed Scopus Google Scholar and p16 H. S. Zhang K. of in in 43: PubMed Scopus Google Scholar et that expression positively correlated with disease severity in S.G. C. W. Zhang J. C. M. W. et senescence-associated beta-galactosidase expression in and disease severity of with J. PubMed Scopus Google Scholar Therefore, senescence may a in the pathogenesis of K. Cellular senescence in Cell. 2017; PubMed Scopus Google Scholar Furthermore, et that of senescent cells in a model the of and the C. M. S. Y. N. et of senescent cells the of and a Med. 2017; PubMed Scopus Google Scholar In tendinopathy, in an increase in human A.J. senescence in human tenocytes inhibition of 1 and activation of the in and in vitro PubMed Scopus Google C.H. Lee S.Y. Yoon K.S. Shin S. Effects of platelet-rich plasma with concomitant use of a corticosteroid on tenocytes from degenerative rotator cuff tears in interleukin tendinopathic conditions.Am. J. Sports Med. 2017; 45: 1141-1150Crossref PubMed Scopus Google Scholar and the than the p16 senescence to the histology of human tendon A.J. senescence in human tenocytes inhibition of 1 and activation of the in and in vitro PubMed Scopus Google Scholar In our the expression of senescent including p53, p21, p16, and SA-β-gal, correlated with tendinopathy severity, that senescence a in tendon of CD44 in a rat Achilles tendinopathy model reduced the expression of senescent and SASP and and lowered ultrasound and that CD44 overexpression tendinopathic tendons SASPs via anti-inflammation and maintenance of homeostasis. Interestingly, the such as and have been shown to senescent cells and the of Y. H. N. Y. M. et of senescent from to Cell. 2015; PubMed Scopus Google Scholar We that tendinopathy in the which hamstring tendons than normal tendons as of the to Therefore, the of with hamstring tendons than that of with tendinopathic and have the expression of senescent markers in the normal the expression of senescent markers increased as tendinopathy in human tendons and rat tenocytes lentiviral CD44 overexpression in the rat model tendinopathy severity, tendinopathic and in the rat tendons and are gene in and clinical with and A. S. L. A. of in lentiviral gene PubMed Scopus Google Scholar lentiviral and gene gene transfer to the tissue of the of in K. lentiviral in human cells are human Ther. PubMed Scopus Google Scholar In to the lentiviral may as 3 and to and J. A. K. R. A and to and Ther. PubMed Scopus Google G. A. A. L. In of lentiviral a type I that gene transfer and 2007; PubMed Scopus Google Scholar Therefore, lentiviral in tendons the of C. C.H. and cell in the gene of chronic Ther. 2007; PubMed Scopus Google Scholar that the in tendinopathic rat tendons of the lentiviral vectors. is to the of in LVCD44-transduced which to the or via the of CD44 levels in rat tendons and the effects of CD44 on tendinopathic the in our animal have the that tendinopathic tendons scores than their model with and in our and were in the and ultrasound feature scores the and Therefore, the in that the lentiviral in rat tendinopathic tendons and our of the effect of the multiple of shown that CD44 is a from tendinopathy via anti-senescence the of CD44 to cell senescence in and with the of and the of the the and from animal were performed in with the the and of of clinical hamstring tendons were from using hamstring tendons as the tendons were the or from a rotator cuff and tendinopathy our tendon and hamstring tendons the were rat tendinopathy were from and in the of and of the were our were and and were with I their Achilles tendons using a to from the the the of M. S. H. stem cells tendinopathy in a rat J. Sports Med. PubMed Scopus Google Scholar or lentiviral and 3 the with an increased of than compared with the normal as an the the rat tendinopathy model C.H. S.Y. is of tendinopathy using a with in a rat 2017; PubMed Scopus Google S.Y. of in a rat Achilles tendinopathy of 2017; PubMed Scopus (12) Google Scholar ultrasound the of tendinopathy and were and the tendinopathic ultrasound characteristics, including and under and were from to as C.H. S.Y. is of tendinopathy using a with in a rat 2017; PubMed Scopus Google S.Y. of in a rat Achilles tendinopathy of 2017; PubMed Scopus (12) Google Scholar and tendinopathic were in the animal and human and rat were in and were with and and examined under a in tenocyte and human a on tenocyte and on a to tendinopathy and and J.L. C.H. S.Y. of CD44 induces and matrix metalloproteinase expression in Biol. PubMed Scopus (12) Google Scholar rat Achilles tendinopathy, a on the C.H. S.Y. is of tendinopathy using a with in a rat 2017; PubMed Scopus Google S.Y. of in a rat Achilles tendinopathy of 2017; PubMed Scopus (12) Google Scholar of the in increased collagen or and or to the clinical or an the and a were and in were activity the were in in in and with p16 and in with with p53, p21, p16, SA-β-gal, and were and in to the of and cells to using of in of rat tendinopathic were with an of I the the Achilles tendons were the were with an of of tendon and tenocyte have been in our J.L. C.H. S.Y. of CD44 induces and matrix metalloproteinase expression in Biol. PubMed Scopus (12) Google S.Y. matrix expression via CD44 in 2017; Google Scholar to cells were in as tendinopathic J.L. C.H. S.Y. of CD44 induces and matrix metalloproteinase expression in Biol. PubMed Scopus (12) Google S.Y. matrix expression via CD44 in 2017; Google Scholar of tenocyte such as cell and with and expression using and tenocyte transfectants in which CD44 is rat lentiviral from control from with and to the the with S.Y. C.R. factor factor activation in the 2015; PubMed Scopus Google Scholar lentiviral and were of cells with and with the and as S.Y. C.R. factor factor activation in the 2015; PubMed Scopus Google Scholar were determined using the of lentiviral tenocytes were with and in the of tendon and as as transfectants in which CD44 were with IL-1β and their senescent using the Senescence Cell and in to the of cells to the of gene transfer in Achilles tendons from with in expression of rat Achilles tendons were with and and the the were and their tendons were to CD44 the in effects of CD44 the rat Achilles tendinopathy model the were to the and the on the of or lentiviral their Achilles tendons in a were to the the ultrasound and were and were the were of the animal and were the first and and of tenocytes and transfectants and tendinopathic tendons and were to with p53, p21, p16, and -3, SA-β-gal, and as in the and in with a and control were using an and using a and the of gene compared with from IL-1β-stimulated and LVCD44-transduced tenocyte transfectants were to to IL-6 expression from rat tenocytes with and using the High with to CD44 IL-6 COX-2 p16 and to the of gene compared with J.L. C.H. S.Y. of CD44 induces and matrix metalloproteinase expression in Biol. PubMed Scopus (12) Google are as the in using the two and were using and of multiple of the the of senescence cells and the of tendinopathy using the to IntroductionThe exact pathophysiology of tendinopathy remains unclear and has been attributed to multiple factors, including mechanical overuse,1Cook J.L. Purdam C.R. Is tendon pathology a continuum? A pathology model to explain the clinical presentation of load-induced tendinopathy.Br. J. Sports Med. 2009; 43: 409-416Crossref PubMed Scopus (612) Google Scholar chronic inflammation,2Dakin S.G. Newton J. Martinez F.O. Hedley R. Gwilym S. Jones N. Reid H.A.B. Wood S. Wells G. Appleton L. et al.Chronic inflammation is a feature of Achilles tendinopathy and rupture.Br. J. Sports Med. 2018; 52: 359-367Crossref PubMed Scopus (88) Google Scholar and aging.3Lui P.P.Y. Wong C.M. Biology of tendon stem cells and tendon in aging.Front. Genet. 2020; 10Crossref PubMed Scopus (12) Google Scholar Cell senescence is an irreversible process in which cell-cycle arrest is attributed to the activation of p16INK4a or p53/p21cip stress-responsive signaling pathways.4Campisi J. d'Adda di Fagagna F. Cellular senescence: when bad things happen to good cells.Nat. Rev. Mol. Cell Biol. 2007; 8: 729-740Crossref PubMed Scopus (2911) Google Scholar Senescent cells have particular characteristics, such as excess secretion of matrix-degrading enzymes and pro-inflammatory cytokines,5Hampel B. Fortschegger K. Ressler S. Chang M.W. Unterluggauer H. Breitwieser A. Sommergruber W. Fitzky B. Lepperdinger G. Jansen-Durr P. et al.Increased expression of extracellular proteins as a hallmark of human endothelial cell in vitro senescence.Exp. Gerontol. 2006; 41: 474-481Crossref PubMed Scopus (60) Google Scholar,6Millis A.J. Hoyle M. McCue H.M. Martini H. Differential expression of metalloproteinase and tissue inhibitor of metalloproteinase genes in aged human fibroblasts.Exp. Cell Res. 1992; 201: 373-379Crossref PubMed Scopus (221) Google Scholar designated senescence-associated secretory phenotypes (SASPs)4Campisi J. d'Adda di Fagagna F. Cellular senescence: when bad things happen to good cells.Nat. Rev. Mol. Cell Biol. 2007; 8: 729-740Crossref PubMed Scopus (2911) Google Scholar and expression of lysosomal senescence-associated β-galactosidase (SA-β-gal).7Lee B.Y. Han J.A. Im J.S. Morrone A. Johung K. Goodwin E.C. Kleijer W.J. DiMaio D. Hwang E.S. Senescence-associated beta-galactosidase is lysosomal beta-galactosidase.Aging Cell. 2006; 5: 187-195Crossref PubMed Scopus (722) Google Scholar Interestingly, many of these SASP cytokines and enzymes, including interleukin (IL)-6 and matrix metalloproteinase (MMP)-1 and -3, are implicated in the pathogenesis of tendinopathy.8Abate M. Silbernagel K.G. Siljeholm C. Di Iorio A. De Amicis D. Salini V. Werner R. Paganelli R. Pathogenesis of tendinopathies: inflammation or degeneration?.Arthritis Res. Ther. 2009; 11: 235Crossref PubMed Scopus (309) Google Scholar,9Wang Y. Tang H. He G. Shi Y. Kang X. Lyu J. Zhou M. Zhu M. Zhang J. Tang K. High concentration of aspirin induces apoptosis in rat tendon stem cells via inhibition of the Wnt/β-catenin pathway.Cell. Physiol. Biochem. 2018; 50: 2046-2059Crossref PubMed Scopus (18) Google Scholar IL-1β, one of the main initiators of tendinopathy, induces IL-6, IL-1β, cyclooxygenase (COX)-2, and MMP-1, -3, and -13 gene expression in human tendon cells and reduces the expression levels of tenomodulin (tnmd) and type 1 and 3 collagen in injured tendon-derived cells.10Tsuzaki M. Guyton G. Garrett W. Archambault J. Herzog W. Almekinders L. Bynum D. Yang X. Banes A.J. IL-1β induces COX2, MMP-1,-3 and-13, ADAMTS-4, IL-1β and IL-6 in human tendon cells.J. Orthop. Res. 2003; 21: 256-264Crossref PubMed Scopus (304) Google Scholar,11Zhang K. Asai S. Yu B. Enomoto-Iwamoto M. IL-1β irreversibly inhibits tenogenic differentiation and alters metabolism in injured tendon-derived progenitor cells in vitro.Biochem. Biophys. Res. Commun. 2015; 463: 667-672Crossref PubMed Scopus (45) Google Scholar Furthermore, IL-1β and dexamethasone, two factors that contribute to tendinopathy, have been shown to increase human tenocyte senescence, either alone or in combination.12Jo C.H. Lee S.Y. Yoon K.S. Shin S. Effects of platelet-rich plasma with concomitant use of a corticosteroid on tenocytes from degenerative rotator cuff tears in interleukin 1beta-induced tendinopathic conditions.Am. J. Sports Med. 2017; 45: 1141-1150Crossref PubMed Scopus (35) Google Scholar Therefore, our first hypothesis that senescence is positively correlated with the of is a which is the of of extracellular matrix M. K. K. Y. to inflammation and Google Scholar the and cell senescence in tendinopathy CD44 signaling have been shown to and and differentiation in aged CD44 signaling and J. PubMed Scopus Google Scholar A that anti-senescence CD44 in human cell M. cell to senescence and PubMed Scopus Google Scholar that CD44 of and expression in IL-1β-stimulated tenocytes and that inhibition of the CD44 using an pro-inflammatory and expression in rat tendinopathic J.L. C.H. S.Y. of CD44 induces and matrix metalloproteinase expression in Biol. PubMed Scopus (12) Google S.Y. matrix expression via CD44 in 2017; Google Scholar Therefore, our hypothesis that CD44 tenocytes from cell senescence under tendinopathic were to the to senescence in tendinopathy and to the of CD44 in SASPs in tendinopathy models. A gene CD44 overexpression that senescence positively correlated with the severity of tendinopathy, and CD44 overexpression protect tendinopathic tendons from SASPs in with anti-inflammation and maintenance of homeostasis.

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