Please use this identifier to cite or link to this item: https://hdl.handle.net/20.500.12530/34603
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dc.contributor.authorVarela-Eirín, Marta
dc.contributor.authorVarela-Vázquez, Adrián
dc.contributor.authorGuitián-Caamaño, Amanda
dc.contributor.authorPaíno, Carlos Luis
dc.contributor.authorMato, Virginia
dc.contributor.authorLargo, Raquel
dc.contributor.authorAasen, Trond
dc.contributor.authorTabernero, Arantxa
dc.contributor.authorFonseca, Eduardo
dc.contributor.authorKandouz, Mustapha
dc.contributor.authorCaeiro, José Ramón
dc.contributor.authorBlanco, Alfonso
dc.contributor.authorMayán, María D
dc.date.accessioned2019-06-28T17:38:44Z-
dc.date.available2019-06-28T17:38:44Z-
dc.date.issued2018-12-05
dc.identifier.citationCell Death Dis.2018 Dec;(9)12:1166
dc.identifier.urihttps://hdl.handle.net/20.500.12530/34603-
dc.description.abstractOsteoarthritis (OA), a chronic disease characterized by articular cartilage degeneration, is a leading cause of disability and pain worldwide. In OA, chondrocytes in cartilage undergo phenotypic changes and senescence, restricting cartilage regeneration and favouring disease progression. Similar to other wound-healing disorders, chondrocytes from OA patients show a chronic increase in the gap junction channel protein connexin43 (Cx43), which regulates signal transduction through the exchange of elements or recruitment/release of signalling factors. Although immature or stem-like cells are present in cartilage from OA patients, their origin and role in disease progression are unknown. In this study, we found that Cx43 acts as a positive regulator of chondrocyte-mesenchymal transition. Overactive Cx43 largely maintains the immature phenotype by increasing nuclear translocation of Twist-1 and tissue remodelling and proinflammatory agents, such as MMPs and IL-1β, which in turn cause cellular senescence through upregulation of p53, p16INK4a and NF-κB, contributing to the senescence-associated secretory phenotype (SASP). Downregulation of either Cx43 by CRISPR/Cas9 or Cx43-mediated gap junctional intercellular communication (GJIC) by carbenoxolone treatment triggered rediferentiation of osteoarthritic chondrocytes into a more differentiated state, associated with decreased synthesis of MMPs and proinflammatory factors, and reduced senescence. We have identified causal Cx43-sensitive circuit in chondrocytes that regulates dedifferentiation, redifferentiation and senescence. We propose that chondrocytes undergo chondrocyte-mesenchymal transition where increased Cx43-mediated GJIC during OA facilitates Twist-1 nuclear translocation as a novel mechanism involved in OA progression. These findings support the use of Cx43 as an appropriate therapeutic target to halt OA progression and to promote cartilage regeneration.
dc.language.isoeng
dc.rightsopenAccess-
dc.titleTargeting of chondrocyte plasticity via connexin43 modulation attenuates cellular senescence and fosters a pro-regenerative environment in osteoarthritis.
dc.typeArtículo
dc.identifier.pubmedID30518918
dc.format.volume9
dc.format.page1166
dc.identifier.e-issn2041-4889
dc.identifier.journalCell death & disease
dc.identifier.doi10.1038/s41419-018-1225-2
dc.format.number12
dc.identifier.pmcPMC6281585
dc.pubmedtypeJournal Article
Appears in Collections:Fundaciones e Institutos de Investigación > IIS H. U. Ramón y Cajal > Artículos

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