<?xml version="1.0" encoding="ISO-8859-1"?><article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance">
<front>
<journal-meta>
<journal-id>1889-836X</journal-id>
<journal-title><![CDATA[Revista de Osteoporosis y Metabolismo Mineral]]></journal-title>
<abbrev-journal-title><![CDATA[Rev Osteoporos Metab Miner]]></abbrev-journal-title>
<issn>1889-836X</issn>
<publisher>
<publisher-name><![CDATA[Sociedad Española de Investigaciones Óseas y Metabolismo Mineral]]></publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id>S1889-836X2019000200003</article-id>
<article-id pub-id-type="doi">10.4321/s1889-836x2019000200003</article-id>
<title-group>
<article-title xml:lang="es"><![CDATA[Regulación de la plasticidad celular y senescencia en condrocitos articulares: conexina 43 como diana terapéutica para el tratamiento de la artrosis]]></article-title>
<article-title xml:lang="en"><![CDATA[A novel therapeutic target for osteoarthritis: control of cellular plasticity and senescence using connexin43]]></article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Varela-Eirín]]></surname>
<given-names><![CDATA[M]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Varela-Vázquez]]></surname>
<given-names><![CDATA[A]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Blanco]]></surname>
<given-names><![CDATA[A]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Caeiro]]></surname>
<given-names><![CDATA[JR]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Mayán]]></surname>
<given-names><![CDATA[MD]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
</contrib-group>
<aff id="A01">
<institution><![CDATA[,Universidad de A Coruña (UDC) Instituto de Investigación Biomédica de A Coruña (INIBIC) Grupo de Investigación Traslacional en Comunicación y Señalización Celular (CellCOM)]]></institution>
<addr-line><![CDATA[A Coruña ]]></addr-line>
<country>España</country>
</aff>
<aff id="A02">
<institution><![CDATA[,Universidad de Dublín Instituto Conway de Investigación Biomédica y Biomolecular ]]></institution>
<addr-line><![CDATA[Dublín ]]></addr-line>
<country>Irlanda</country>
</aff>
<aff id="A03">
<institution><![CDATA[,Universidad de Santiago de Compostela (USC) Complejo Hospitalario Universitario de Santiago de Compostela Departamento de Cirugía Ortopédica y Traumatología]]></institution>
<addr-line><![CDATA[Santiago de Compostela ]]></addr-line>
<country>España</country>
</aff>
<pub-date pub-type="pub">
<day>00</day>
<month>06</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="epub">
<day>00</day>
<month>06</month>
<year>2019</year>
</pub-date>
<volume>11</volume>
<numero>2</numero>
<fpage>46</fpage>
<lpage>54</lpage>
<copyright-statement/>
<copyright-year/>
<self-uri xlink:href="http://scielo.isciii.es/scielo.php?script=sci_arttext&amp;pid=S1889-836X2019000200003&amp;lng=en&amp;nrm=iso"></self-uri><self-uri xlink:href="http://scielo.isciii.es/scielo.php?script=sci_abstract&amp;pid=S1889-836X2019000200003&amp;lng=en&amp;nrm=iso"></self-uri><self-uri xlink:href="http://scielo.isciii.es/scielo.php?script=sci_pdf&amp;pid=S1889-836X2019000200003&amp;lng=en&amp;nrm=iso"></self-uri><abstract abstract-type="short" xml:lang="es"><p><![CDATA[Resumen Introducción: La artrosis (OA) es una enfermedad musculoesquelética degenerativa que afecta aproximadamente al 13% de la población occidental. A día de hoy no existe un tratamiento eficaz que evite el progreso de la misma o facilite la regeneración del cartílago articular. La conexina43 (Cx43) es una proteína transmembrana que se encuentra en niveles elevados en el cartílago y en la membrana sinovial de pacientes con OA. Esta proteína forma canales que permiten el intercambio de moléculas e iones entre dos células en contacto o entre la célula y su entorno, denominados uniones comunicantes (UCs) y hemicanales, respectivamente. En este estudio se investigó la función de la Cx43 y de las UCs en la degradación del cartílago articular de pacientes con OA. Material y métodos: Se han aislado condrocitos primarios del cartílago de donantes OA y sanos. Se evaluaron los niveles proteicos mediante Western blot, inmunofluorescencia y citometría de flujo. La expresión génica se ha evaluado mediante RT-qPCR, mientras que la comunicación celular se estudió mediante el ensayo scrape loading/dye transfer. La senescencia celular se evaluó midiendo la actividad de la &#946;galactosidasa mediante citometría celular o microscopía. Resultados: Los resultados obtenidos indican que la sobreactividad de la Cx43 y de la comunicación intercelular a través de UCs detectadas en OA están implicadas con el progreso de la enfermedad al activar procesos de desdiferenciación celular hacia un estado inmaduro y senescencia celular. Utilizando condrocitos en cultivo aislados del cartílago de donantes con OA hemos demostrado que el incremento de la Cx43 activa factores implicados en la transición epitelio-mesénquima (TEM), como el factor de transcripción Twist-1. El incremento en el número de células desdiferenciadas y con altos índices de proliferación celular desencadena en senescencia celular vía p53/p16INK4a, activando el fenotipo secretor asociado a senescencia (SASP, del inglés Senescence-Associated Secretory Phenotype) que incluye la síntesis y liberación de factores inflamatorios como la interleuquina 6 (IL-6). La disminución de los niveles de la Cx43 utilizando pequeñas moléculas como la oleuropeína o técnicas de edición genética como CRISPR/Cas9 revirtió el proceso dando lugar a rediferenciación celular, mejorando el fenotipo celular con incremento en proteínas implicadas en formación del tejido y diminuyendo la síntesis de MMPs y del componente inflamatorio y senescencia. Conclusiones: La disminución de la Cx43 en condrocitos artrósicos restaura regeneración tisular, por activación de rediferenciación celular y disminución de senescencia. Estos resultados corroboran el uso de la Cx43 como una diana terapéutica eficaz para restaurar regeneración del cartílago en pacientes con OA y evitar la progresión de la enfermedad.]]></p></abstract>
<abstract abstract-type="short" xml:lang="en"><p><![CDATA[Summary Introduction: Osteoarthritis (OA) is a degenerative musculoskeletal disease, which affects approximately the 13% of western population. Nowadays, there is no effective treatment for OA to avoid disease progression or to promote cartilage regeneration. Connexin43 (Cx43) is a transmembrane protein increased in cartilage and synovium from OA patients. Cx43 forms membrane channels that allow the exchange of molecules and ions between two adjacent cells through gap junctions (GJs), or between a cell and its environment through hemichannels. In this study we investigated the involvement of Cx43 and GJ intercellular communication in the degradation of articular cartilage in chondrocytes from patients with OA. Material and methods: Primary chondrocytes were obtained from cartilage from OA and healthy donors. Protein levels were evaluated by western-blot, immunofluorescence and flow cytometry. RNA expression was evaluated by RT-qPCR. A scrape loading/dye transfer assay was used to evaluate cell communication. Cell senescence was analysed by flow cytometry or by light microscopy using &#946;galactosidase assay. Results: Cx43 and GJs overactivities were correlated with the progression of OA, by promoting chronic cell dedifferentiation and senescence in vitro assays. We found that Cx43 overexpression activates factors involved in epithelial-to-mesenchymal transition, such as Twist-1. Increased levels of dedifferentiated cells, with high rates of cell proliferation, led to cell senescence via p53/p16INK4a, activating the senescence-associated secretory phenotype (SASP) and promoting the synthesis and liberation of inflammatory factors, including the interleukin-6 (IL-6). Cx43 downregulation by using small molecules, such as oleuropein, or by genetic edition with CRISPR technology, led to the chondrocyte redifferentiation and an improved phenotype, with increased synthesis of extracellular matrix proteins such as Col2A1 and downregulating the synthesis of MMPs, inflammation and senescence. Conclusions: Downregulation of Cx43 in OA chondrocytes restores regeneration by activating chondrocyte re-differentiation and decreasing cellular senescence. These results corroborate the use of Cx43 as an effective therapeutic target in order to restore cartilage regeneration and avoid OA progression.]]></p></abstract>
<kwd-group>
<kwd lng="es"><![CDATA[conexina43]]></kwd>
<kwd lng="es"><![CDATA[artrosis]]></kwd>
<kwd lng="es"><![CDATA[desdiferenciación]]></kwd>
<kwd lng="es"><![CDATA[senescencia]]></kwd>
<kwd lng="es"><![CDATA[regeneración tisular]]></kwd>
<kwd lng="en"><![CDATA[connexin43]]></kwd>
<kwd lng="en"><![CDATA[osteoarthritis]]></kwd>
<kwd lng="en"><![CDATA[dedifferentiation]]></kwd>
<kwd lng="en"><![CDATA[senescence]]></kwd>
<kwd lng="en"><![CDATA[tissue regeneration]]></kwd>
</kwd-group>
</article-meta>
</front><back>
<ref-list>
<ref id="B1">
<label>1</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Kapoor]]></surname>
<given-names><![CDATA[M]]></given-names>
</name>
<name>
<surname><![CDATA[Martel-Pelletier]]></surname>
<given-names><![CDATA[J]]></given-names>
</name>
<name>
<surname><![CDATA[Lajeu-nesse]]></surname>
<given-names><![CDATA[D]]></given-names>
</name>
<name>
<surname><![CDATA[Pelletier]]></surname>
<given-names><![CDATA[JP]]></given-names>
</name>
<name>
<surname><![CDATA[Fahmi]]></surname>
<given-names><![CDATA[H]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[Role of proinflammatory cytokines in the pathophysiology of osteoarthritis]]></article-title>
<source><![CDATA[Nat Rev Rheumatol]]></source>
<year>2011</year>
<volume>7</volume>
<numero>1</numero>
<issue>1</issue>
<page-range>33-42</page-range></nlm-citation>
</ref>
<ref id="B2">
<label>2</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Loeser]]></surname>
<given-names><![CDATA[RF]]></given-names>
</name>
<name>
<surname><![CDATA[Collins]]></surname>
<given-names><![CDATA[JA]]></given-names>
</name>
<name>
<surname><![CDATA[Diekman]]></surname>
<given-names><![CDATA[BO]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[Ageing and the pathogenesis of osteoarthritis]]></article-title>
<source><![CDATA[Nat Rev Rheumatol]]></source>
<year>2016</year>
<volume>12</volume>
<numero>7</numero>
<issue>7</issue>
<page-range>412-20</page-range></nlm-citation>
</ref>
<ref id="B3">
<label>3</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Philipot]]></surname>
<given-names><![CDATA[D]]></given-names>
</name>
<name>
<surname><![CDATA[Guerit]]></surname>
<given-names><![CDATA[D]]></given-names>
</name>
<name>
<surname><![CDATA[Platano]]></surname>
<given-names><![CDATA[D]]></given-names>
</name>
<name>
<surname><![CDATA[Chu-chana]]></surname>
<given-names><![CDATA[P]]></given-names>
</name>
<name>
<surname><![CDATA[Olivotto]]></surname>
<given-names><![CDATA[E]]></given-names>
</name>
<name>
<surname><![CDATA[Espinoza]]></surname>
<given-names><![CDATA[F]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[p16INK4a and its regulator miR-24 link senescence and chondrocyte terminal differentiation-associated matrix remodeling in osteoarthritis]]></article-title>
<source><![CDATA[Arthritis Res Ther]]></source>
<year>2014</year>
<volume>16</volume>
<numero>1</numero>
<issue>1</issue>
<page-range>R58</page-range></nlm-citation>
</ref>
<ref id="B4">
<label>4</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Mayan]]></surname>
<given-names><![CDATA[MD]]></given-names>
</name>
<name>
<surname><![CDATA[Gago-Fuentes]]></surname>
<given-names><![CDATA[R]]></given-names>
</name>
<name>
<surname><![CDATA[Carpin-tero-Fernandez]]></surname>
<given-names><![CDATA[P]]></given-names>
</name>
<name>
<surname><![CDATA[Fernandez-Puente]]></surname>
<given-names><![CDATA[P]]></given-names>
</name>
<name>
<surname><![CDATA[Filgueira-Fernandez]]></surname>
<given-names><![CDATA[P]]></given-names>
</name>
<name>
<surname><![CDATA[Goyanes]]></surname>
<given-names><![CDATA[N]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[Articular chondrocyte network mediated by gap junctions: role in metabolic cartilage homeostasis]]></article-title>
<source><![CDATA[Ann Rheum Dis]]></source>
<year>2013</year>
</nlm-citation>
</ref>
<ref id="B5">
<label>5</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Chi]]></surname>
<given-names><![CDATA[SS]]></given-names>
</name>
<name>
<surname><![CDATA[Rattner]]></surname>
<given-names><![CDATA[JB]]></given-names>
</name>
<name>
<surname><![CDATA[Matyas]]></surname>
<given-names><![CDATA[JR]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[Communication between paired chondrocytes in the superficial zone of articular cartilage]]></article-title>
<source><![CDATA[J Anat]]></source>
<year>2004</year>
<volume>205</volume>
<numero>5</numero>
<issue>5</issue>
<page-range>363-70</page-range></nlm-citation>
</ref>
<ref id="B6">
<label>6</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Mayan]]></surname>
<given-names><![CDATA[MD]]></given-names>
</name>
<name>
<surname><![CDATA[Carpintero-Fernandez]]></surname>
<given-names><![CDATA[P]]></given-names>
</name>
<name>
<surname><![CDATA[Gago-Fuentes]]></surname>
<given-names><![CDATA[R]]></given-names>
</name>
<name>
<surname><![CDATA[Martinez-de-Ilarduya]]></surname>
<given-names><![CDATA[O]]></given-names>
</name>
<name>
<surname><![CDATA[Wang]]></surname>
<given-names><![CDATA[HZ]]></given-names>
</name>
<name>
<surname><![CDATA[Valiunas]]></surname>
<given-names><![CDATA[V]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[Human articular chondrocytes express multiple gap junction proteins: differential expression of connexins in normal and osteoarthritic cartilage]]></article-title>
<source><![CDATA[Am J Pathol]]></source>
<year>2013</year>
<volume>182</volume>
<numero>4</numero>
<issue>4</issue>
<page-range>1337-46</page-range></nlm-citation>
</ref>
<ref id="B7">
<label>7</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Gago-Fuentes]]></surname>
<given-names><![CDATA[R]]></given-names>
</name>
<name>
<surname><![CDATA[Bechberger]]></surname>
<given-names><![CDATA[JF]]></given-names>
</name>
<name>
<surname><![CDATA[Varela-Eirin]]></surname>
<given-names><![CDATA[M]]></given-names>
</name>
<name>
<surname><![CDATA[Varela-Vazquez]]></surname>
<given-names><![CDATA[A]]></given-names>
</name>
<name>
<surname><![CDATA[Acea]]></surname>
<given-names><![CDATA[B]]></given-names>
</name>
<name>
<surname><![CDATA[Fonseca]]></surname>
<given-names><![CDATA[E]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[The C-terminal domain of connexin43 modulates cartilage structure via chondrocyte phenotypic changes]]></article-title>
<source><![CDATA[Oncotarget]]></source>
<year>2016</year>
<volume>7</volume>
<numero>45</numero>
<issue>45</issue>
</nlm-citation>
</ref>
<ref id="B8">
<label>8</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Mendoza-Naranjo]]></surname>
<given-names><![CDATA[A]]></given-names>
</name>
<name>
<surname><![CDATA[Cormie]]></surname>
<given-names><![CDATA[P]]></given-names>
</name>
<name>
<surname><![CDATA[Serrano]]></surname>
<given-names><![CDATA[AE]]></given-names>
</name>
<name>
<surname><![CDATA[Wang]]></surname>
<given-names><![CDATA[CM]]></given-names>
</name>
<name>
<surname><![CDATA[Thrasivoulou]]></surname>
<given-names><![CDATA[C]]></given-names>
</name>
<name>
<surname><![CDATA[Sutcliffe]]></surname>
<given-names><![CDATA[JE]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[Overexpression of the gap junction protein Cx43 as found in diabetic foot ulcers can retard fibroblast migration]]></article-title>
<source><![CDATA[Cell Biol Int]]></source>
<year>2012</year>
<volume>36</volume>
<numero>7</numero>
<issue>7</issue>
<page-range>661-7</page-range></nlm-citation>
</ref>
<ref id="B9">
<label>9</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Brandner]]></surname>
<given-names><![CDATA[JM]]></given-names>
</name>
<name>
<surname><![CDATA[Houdek]]></surname>
<given-names><![CDATA[P]]></given-names>
</name>
<name>
<surname><![CDATA[Husing]]></surname>
<given-names><![CDATA[B]]></given-names>
</name>
<name>
<surname><![CDATA[Kaiser]]></surname>
<given-names><![CDATA[C]]></given-names>
</name>
<name>
<surname><![CDATA[Moll]]></surname>
<given-names><![CDATA[I]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[Connexins 26, 30, and 43: differences among spontaneous, chronic, and accelerated human wound healing]]></article-title>
<source><![CDATA[J Invest Dermatol]]></source>
<year>2004</year>
<volume>122</volume>
<numero>5</numero>
<issue>5</issue>
<page-range>1310-20</page-range></nlm-citation>
</ref>
<ref id="B10">
<label>10</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Rai]]></surname>
<given-names><![CDATA[MF]]></given-names>
</name>
<name>
<surname><![CDATA[Schmidt]]></surname>
<given-names><![CDATA[EJ]]></given-names>
</name>
<name>
<surname><![CDATA[McAlinden]]></surname>
<given-names><![CDATA[A]]></given-names>
</name>
<name>
<surname><![CDATA[Che-verud]]></surname>
<given-names><![CDATA[JM]]></given-names>
</name>
<name>
<surname><![CDATA[Sandell]]></surname>
<given-names><![CDATA[LJ]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[Molecular insight into the association between cartilage regeneration and ear wound healing in genetic mouse models: targeting new genes in regeneration]]></article-title>
<source><![CDATA[G3]]></source>
<year>2013</year>
<volume>3</volume>
<numero>11</numero>
<issue>11</issue>
<page-range>1881-91</page-range></nlm-citation>
</ref>
<ref id="B11">
<label>11</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Rai]]></surname>
<given-names><![CDATA[MF]]></given-names>
</name>
<name>
<surname><![CDATA[Sandell]]></surname>
<given-names><![CDATA[LJ]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[Regeneration of articular cartilage in healer and non-healer mice]]></article-title>
<source><![CDATA[Matrix Biol]]></source>
<year>2014</year>
<volume>39</volume>
<page-range>50-5</page-range></nlm-citation>
</ref>
<ref id="B12">
<label>12</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Grogan]]></surname>
<given-names><![CDATA[SP]]></given-names>
</name>
<name>
<surname><![CDATA[Miyaki]]></surname>
<given-names><![CDATA[S]]></given-names>
</name>
<name>
<surname><![CDATA[Asahara]]></surname>
<given-names><![CDATA[H]]></given-names>
</name>
<name>
<surname><![CDATA[D'-Lima]]></surname>
<given-names><![CDATA[DD]]></given-names>
</name>
<name>
<surname><![CDATA[Lotz]]></surname>
<given-names><![CDATA[MK]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[Mesenchymal progenitor cell markers in human articular cartilage: normal distribution and changes in osteoarthritis]]></article-title>
<source><![CDATA[Arthritis Res Ther]]></source>
<year>2009</year>
<volume>11</volume>
<numero>3</numero>
<issue>3</issue>
<page-range>R85</page-range></nlm-citation>
</ref>
<ref id="B13">
<label>13</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Kim]]></surname>
<given-names><![CDATA[AC]]></given-names>
</name>
<name>
<surname><![CDATA[Spector]]></surname>
<given-names><![CDATA[M]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[Distribution of chondrocytes containing alpha-smooth muscle actin in human articular cartilage]]></article-title>
<source><![CDATA[J Orthop Res]]></source>
<year>2000</year>
<volume>18</volume>
<numero>5</numero>
<issue>5</issue>
<page-range>749-55</page-range></nlm-citation>
</ref>
<ref id="B14">
<label>14</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Bae]]></surname>
<given-names><![CDATA[DK]]></given-names>
</name>
<name>
<surname><![CDATA[Yoon]]></surname>
<given-names><![CDATA[KH]]></given-names>
</name>
<name>
<surname><![CDATA[Song]]></surname>
<given-names><![CDATA[SJ]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[Cartilage healing after microfracture in osteo-arthritic knees]]></article-title>
<source><![CDATA[Arthroscopy]]></source>
<year>2006</year>
<volume>22</volume>
<numero>4</numero>
<issue>4</issue>
<page-range>367-74</page-range></nlm-citation>
</ref>
<ref id="B15">
<label>15</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Bank]]></surname>
<given-names><![CDATA[RA]]></given-names>
</name>
<name>
<surname><![CDATA[Soudry]]></surname>
<given-names><![CDATA[M]]></given-names>
</name>
<name>
<surname><![CDATA[Maroudas]]></surname>
<given-names><![CDATA[A]]></given-names>
</name>
<name>
<surname><![CDATA[Mizrahi]]></surname>
<given-names><![CDATA[J]]></given-names>
</name>
<name>
<surname><![CDATA[TeKoppele]]></surname>
<given-names><![CDATA[JM]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[The increased swelling and instantaneous deformation of osteoarthritic cartilage is highly correlated with collagen degradation]]></article-title>
<source><![CDATA[Arthritis Rheum]]></source>
<year>2000</year>
<volume>43</volume>
<numero>10</numero>
<issue>10</issue>
<page-range>2202-10</page-range></nlm-citation>
</ref>
<ref id="B16">
<label>16</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Barley]]></surname>
<given-names><![CDATA[RD]]></given-names>
</name>
<name>
<surname><![CDATA[Adesida]]></surname>
<given-names><![CDATA[AB]]></given-names>
</name>
<name>
<surname><![CDATA[Bagnall]]></surname>
<given-names><![CDATA[KM]]></given-names>
</name>
<name>
<surname><![CDATA[Jomha]]></surname>
<given-names><![CDATA[NM]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[Immunohistochemical characterization of reparative tissue present in human osteoarthritic tissue]]></article-title>
<source><![CDATA[Virchows Archiv]]></source>
<year>2010</year>
<volume>456</volume>
<numero>5</numero>
<issue>5</issue>
<page-range>561-9</page-range></nlm-citation>
</ref>
<ref id="B17">
<label>17</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Heinegard]]></surname>
<given-names><![CDATA[D]]></given-names>
</name>
<name>
<surname><![CDATA[Saxne]]></surname>
<given-names><![CDATA[T]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[The role of the cartilage matrix in osteoarthritis]]></article-title>
<source><![CDATA[Nat Rev Rheumatol]]></source>
<year>2011</year>
<volume>7</volume>
<numero>1</numero>
<issue>1</issue>
<page-range>50-6</page-range></nlm-citation>
</ref>
<ref id="B18">
<label>18</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Garciadiego-Cazares]]></surname>
<given-names><![CDATA[D]]></given-names>
</name>
<name>
<surname><![CDATA[Aguirre-San-chez]]></surname>
<given-names><![CDATA[HI]]></given-names>
</name>
<name>
<surname><![CDATA[Abarca-Buis]]></surname>
<given-names><![CDATA[RF]]></given-names>
</name>
<name>
<surname><![CDATA[Kouri]]></surname>
<given-names><![CDATA[JB]]></given-names>
</name>
<name>
<surname><![CDATA[Velas-quillo]]></surname>
<given-names><![CDATA[C]]></given-names>
</name>
<name>
<surname><![CDATA[Ibarra]]></surname>
<given-names><![CDATA[C]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[Regulation of alpha5 and alphaV Integrin Expression by GDF-5 and BMP-7 in Chondrocyte Differentiation and Osteoarthritis]]></article-title>
<source><![CDATA[PLoS One]]></source>
<year>2015</year>
<volume>10</volume>
<numero>5</numero>
<issue>5</issue>
</nlm-citation>
</ref>
<ref id="B19">
<label>19</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Grenier]]></surname>
<given-names><![CDATA[S]]></given-names>
</name>
<name>
<surname><![CDATA[Bhargava]]></surname>
<given-names><![CDATA[MM]]></given-names>
</name>
<name>
<surname><![CDATA[Torzilli]]></surname>
<given-names><![CDATA[PA]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[An in vitro model for the pathological degradation of articular cartilage in osteoarthritis]]></article-title>
<source><![CDATA[J Biomech]]></source>
<year>2014</year>
<volume>47</volume>
<numero>3</numero>
<issue>3</issue>
<page-range>645-52</page-range></nlm-citation>
</ref>
<ref id="B20">
<label>20</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Johnson]]></surname>
<given-names><![CDATA[K]]></given-names>
</name>
<name>
<surname><![CDATA[Zhu]]></surname>
<given-names><![CDATA[S]]></given-names>
</name>
<name>
<surname><![CDATA[Tremblay]]></surname>
<given-names><![CDATA[MS]]></given-names>
</name>
<name>
<surname><![CDATA[Payette]]></surname>
<given-names><![CDATA[JN]]></given-names>
</name>
<name>
<surname><![CDATA[Wang]]></surname>
<given-names><![CDATA[J]]></given-names>
</name>
<name>
<surname><![CDATA[Bouchez]]></surname>
<given-names><![CDATA[LC]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[A stem cell-based approach to cartilage repair]]></article-title>
<source><![CDATA[Science]]></source>
<year>2012</year>
<volume>336</volume>
<numero>6082</numero>
<issue>6082</issue>
<page-range>717-21</page-range></nlm-citation>
</ref>
<ref id="B21">
<label>21</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Yano]]></surname>
<given-names><![CDATA[F]]></given-names>
</name>
<name>
<surname><![CDATA[Hojo]]></surname>
<given-names><![CDATA[H]]></given-names>
</name>
<name>
<surname><![CDATA[Ohba]]></surname>
<given-names><![CDATA[S]]></given-names>
</name>
<name>
<surname><![CDATA[Fukai]]></surname>
<given-names><![CDATA[A]]></given-names>
</name>
<name>
<surname><![CDATA[Hosaka]]></surname>
<given-names><![CDATA[Y]]></given-names>
</name>
<name>
<surname><![CDATA[Ikeda]]></surname>
<given-names><![CDATA[T]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[A novel disease-modifying osteoarthritis drug candidate targeting Runx1]]></article-title>
<source><![CDATA[Ann Rheum Dis]]></source>
<year>2013</year>
<volume>72</volume>
<numero>5</numero>
<issue>5</issue>
<page-range>748-53</page-range></nlm-citation>
</ref>
<ref id="B22">
<label>22</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Kitamura]]></surname>
<given-names><![CDATA[H]]></given-names>
</name>
<name>
<surname><![CDATA[Okazaki]]></surname>
<given-names><![CDATA[M]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[AG-041R, a novel indoline-2-one derivative, stimulates chondrogenesis in a bipotent chondroprogenitor cell line CL-1]]></article-title>
<source><![CDATA[Osteoarthritis Cartilage]]></source>
<year>2005</year>
<volume>13</volume>
<numero>4</numero>
<issue>4</issue>
<page-range>287-96</page-range></nlm-citation>
</ref>
<ref id="B23">
<label>23</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Bellesini]]></surname>
<given-names><![CDATA[LS]]></given-names>
</name>
<name>
<surname><![CDATA[Beloti]]></surname>
<given-names><![CDATA[MM]]></given-names>
</name>
<name>
<surname><![CDATA[Crippa]]></surname>
<given-names><![CDATA[GE]]></given-names>
</name>
<name>
<surname><![CDATA[Bombonato-Prado]]></surname>
<given-names><![CDATA[KF]]></given-names>
</name>
<name>
<surname><![CDATA[Junta]]></surname>
<given-names><![CDATA[CM]]></given-names>
</name>
<name>
<surname><![CDATA[Marques]]></surname>
<given-names><![CDATA[MM]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[The effect of TAK-778 on gene expression of osteoblastic cells is mediated through estrogen receptor]]></article-title>
<source><![CDATA[Exp Biol Med (Maywood)]]></source>
<year>2009</year>
<volume>234</volume>
<numero>2</numero>
<issue>2</issue>
<page-range>190-9</page-range></nlm-citation>
</ref>
<ref id="B24">
<label>24</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Gangoso]]></surname>
<given-names><![CDATA[E]]></given-names>
</name>
<name>
<surname><![CDATA[Thirant]]></surname>
<given-names><![CDATA[C]]></given-names>
</name>
<name>
<surname><![CDATA[Chneiweiss]]></surname>
<given-names><![CDATA[H]]></given-names>
</name>
<name>
<surname><![CDATA[Medina]]></surname>
<given-names><![CDATA[JM]]></given-names>
</name>
<name>
<surname><![CDATA[Tabernero]]></surname>
<given-names><![CDATA[A]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[A cell-penetrating peptide based on the interaction between c-Src and connexin43 reverses glioma stem cell phenotype]]></article-title>
<source><![CDATA[Cell Death Dis]]></source>
<year>2014</year>
<volume>5</volume>
</nlm-citation>
</ref>
<ref id="B25">
<label>25</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Cheng]]></surname>
<given-names><![CDATA[F]]></given-names>
</name>
<name>
<surname><![CDATA[Shen]]></surname>
<given-names><![CDATA[Y]]></given-names>
</name>
<name>
<surname><![CDATA[Mohanasundaram]]></surname>
<given-names><![CDATA[P]]></given-names>
</name>
<name>
<surname><![CDATA[Lindstrom]]></surname>
<given-names><![CDATA[M]]></given-names>
</name>
<name>
<surname><![CDATA[Ivaska]]></surname>
<given-names><![CDATA[J]]></given-names>
</name>
<name>
<surname><![CDATA[Ny]]></surname>
<given-names><![CDATA[T]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[Vi-mentin coordinates fibroblast proliferation and keratinocyte differentiation in wound healing via TGF-beta-Slug signaling]]></article-title>
<source><![CDATA[Proc Natl Acad Sci U S A.]]></source>
<year>2016</year>
<volume>113</volume>
<numero>30</numero>
<issue>30</issue>
</nlm-citation>
</ref>
<ref id="B26">
<label>26</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Gurtner]]></surname>
<given-names><![CDATA[GC]]></given-names>
</name>
<name>
<surname><![CDATA[Werner]]></surname>
<given-names><![CDATA[S]]></given-names>
</name>
<name>
<surname><![CDATA[Barrandon]]></surname>
<given-names><![CDATA[Y]]></given-names>
</name>
<name>
<surname><![CDATA[Longaker]]></surname>
<given-names><![CDATA[MT]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[Wound repair and regeneration]]></article-title>
<source><![CDATA[Nature]]></source>
<year>2008</year>
<volume>453</volume>
<numero>7193</numero>
<issue>7193</issue>
<page-range>314-21</page-range></nlm-citation>
</ref>
<ref id="B27">
<label>27</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Li]]></surname>
<given-names><![CDATA[M]]></given-names>
</name>
<name>
<surname><![CDATA[Luan]]></surname>
<given-names><![CDATA[F]]></given-names>
</name>
<name>
<surname><![CDATA[Zhao]]></surname>
<given-names><![CDATA[Y]]></given-names>
</name>
<name>
<surname><![CDATA[Hao]]></surname>
<given-names><![CDATA[H]]></given-names>
</name>
<name>
<surname><![CDATA[Zhou]]></surname>
<given-names><![CDATA[Y]]></given-names>
</name>
<name>
<surname><![CDATA[Han]]></surname>
<given-names><![CDATA[W]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[Epithelial-mesenchymal transition: An emerging target in tissue fibrosis]]></article-title>
<source><![CDATA[Exp Biol Med (Maywood)]]></source>
<year>2016</year>
<volume>241</volume>
<numero>1</numero>
<issue>1</issue>
<page-range>1-13</page-range></nlm-citation>
</ref>
<ref id="B28">
<label>28</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Ye]]></surname>
<given-names><![CDATA[X]]></given-names>
</name>
<name>
<surname><![CDATA[Weinberg]]></surname>
<given-names><![CDATA[RA]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[Epithelial-Mesenchymal Plasticity: A Central Regulator of Cancer Progression]]></article-title>
<source><![CDATA[Trends Cell Biol]]></source>
<year>2015</year>
<volume>25</volume>
<numero>11</numero>
<issue>11</issue>
<page-range>675-86</page-range></nlm-citation>
</ref>
<ref id="B29">
<label>29</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Price]]></surname>
<given-names><![CDATA[JS]]></given-names>
</name>
<name>
<surname><![CDATA[Waters]]></surname>
<given-names><![CDATA[JG]]></given-names>
</name>
<name>
<surname><![CDATA[Darrah]]></surname>
<given-names><![CDATA[C]]></given-names>
</name>
<name>
<surname><![CDATA[Pennington]]></surname>
<given-names><![CDATA[C]]></given-names>
</name>
<name>
<surname><![CDATA[Edwards]]></surname>
<given-names><![CDATA[DR]]></given-names>
</name>
<name>
<surname><![CDATA[Donell]]></surname>
<given-names><![CDATA[ST]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[The role of chondrocyte senescence in osteoarthritis]]></article-title>
<source><![CDATA[Aging Cell]]></source>
<year>2002</year>
<volume>1</volume>
<numero>1</numero>
<issue>1</issue>
<page-range>57-65</page-range></nlm-citation>
</ref>
<ref id="B30">
<label>30</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Zhou]]></surname>
<given-names><![CDATA[HW]]></given-names>
</name>
<name>
<surname><![CDATA[Lou]]></surname>
<given-names><![CDATA[SQ]]></given-names>
</name>
<name>
<surname><![CDATA[Zhang]]></surname>
<given-names><![CDATA[K]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[Recovery of function in osteoarthritic chondrocytes induced by p16INK4a-spe-cific siRNA in vitro]]></article-title>
<source><![CDATA[Rheumatology]]></source>
<year>2004</year>
<volume>43</volume>
<numero>5</numero>
<issue>5</issue>
<page-range>555-68</page-range><publisher-loc><![CDATA[Oxford ]]></publisher-loc>
</nlm-citation>
</ref>
<ref id="B31">
<label>31</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Gao]]></surname>
<given-names><![CDATA[SG]]></given-names>
</name>
<name>
<surname><![CDATA[Zeng]]></surname>
<given-names><![CDATA[C]]></given-names>
</name>
<name>
<surname><![CDATA[Li]]></surname>
<given-names><![CDATA[LJ]]></given-names>
</name>
<name>
<surname><![CDATA[Luo]]></surname>
<given-names><![CDATA[W]]></given-names>
</name>
<name>
<surname><![CDATA[Zhang]]></surname>
<given-names><![CDATA[FJ]]></given-names>
</name>
<name>
<surname><![CDATA[Tian]]></surname>
<given-names><![CDATA[J]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[Correlation between senescence-associated beta-galactosi-dase expression in articular cartilage and disease severity of patients with knee osteoarthritis]]></article-title>
<source><![CDATA[Int J Rheum Dis]]></source>
<year>2016</year>
<volume>19</volume>
<numero>3</numero>
<issue>3</issue>
<page-range>226-32</page-range></nlm-citation>
</ref>
<ref id="B32">
<label>32</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Xu]]></surname>
<given-names><![CDATA[M]]></given-names>
</name>
<name>
<surname><![CDATA[Bradley]]></surname>
<given-names><![CDATA[EW]]></given-names>
</name>
<name>
<surname><![CDATA[Weivoda]]></surname>
<given-names><![CDATA[MM]]></given-names>
</name>
<name>
<surname><![CDATA[Hwang]]></surname>
<given-names><![CDATA[SM]]></given-names>
</name>
<name>
<surname><![CDATA[Pirtskhalava]]></surname>
<given-names><![CDATA[T]]></given-names>
</name>
<name>
<surname><![CDATA[Decklever]]></surname>
<given-names><![CDATA[T]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[Transplanted Senescent Cells Induce an Osteoarthritis-Like Condition in Mice]]></article-title>
<source><![CDATA[J Gerontol A S Biol Sci Med Sci]]></source>
<year>2017</year>
<volume>72</volume>
<numero>6</numero>
<issue>6</issue>
<page-range>780-5</page-range></nlm-citation>
</ref>
<ref id="B33">
<label>33</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Jeon]]></surname>
<given-names><![CDATA[OH]]></given-names>
</name>
<name>
<surname><![CDATA[Kim]]></surname>
<given-names><![CDATA[C]]></given-names>
</name>
<name>
<surname><![CDATA[Laberge]]></surname>
<given-names><![CDATA[RM]]></given-names>
</name>
<name>
<surname><![CDATA[Demaria]]></surname>
<given-names><![CDATA[M]]></given-names>
</name>
<name>
<surname><![CDATA[Rathod]]></surname>
<given-names><![CDATA[S]]></given-names>
</name>
<name>
<surname><![CDATA[Vasserot]]></surname>
<given-names><![CDATA[AP]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment]]></article-title>
<source><![CDATA[Nat Med]]></source>
<year>2017</year>
<volume>23</volume>
<numero>6</numero>
<issue>6</issue>
<page-range>775-81</page-range></nlm-citation>
</ref>
<ref id="B34">
<label>34</label><nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname><![CDATA[Toh]]></surname>
<given-names><![CDATA[WS]]></given-names>
</name>
<name>
<surname><![CDATA[Brittberg]]></surname>
<given-names><![CDATA[M]]></given-names>
</name>
<name>
<surname><![CDATA[Farr]]></surname>
<given-names><![CDATA[J]]></given-names>
</name>
<name>
<surname><![CDATA[Foldager]]></surname>
<given-names><![CDATA[CB]]></given-names>
</name>
<name>
<surname><![CDATA[Gomoll]]></surname>
<given-names><![CDATA[AH]]></given-names>
</name>
<name>
<surname><![CDATA[Hui]]></surname>
<given-names><![CDATA[JH]]></given-names>
</name>
</person-group>
<article-title xml:lang=""><![CDATA[Cellular senescence in aging and osteoarthritis]]></article-title>
<source><![CDATA[Acta Orthop]]></source>
<year>2016</year>
<volume>87</volume>
<numero>363</numero>
<issue>363</issue>
<page-range>6-14</page-range></nlm-citation>
</ref>
</ref-list>
</back>
</article>
