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Targeting of chondrocyte plasticity via connexin43 modulation attenuates cellular senescence and fosters a pro-regenerative environment in osteoarthritis
dc.contributor.author | Varela-Eirín, Marta | |
dc.contributor.author | Varela Vázquez, Adrián | |
dc.contributor.author | Guitián-Caamaño, Amanda | |
dc.contributor.author | Luis Paíno, Carlos | |
dc.contributor.author | Mato-Abad, Virginia | |
dc.contributor.author | Largo, Raquel | |
dc.contributor.author | Aasen, Trond | |
dc.contributor.author | Tabernero, Arantxa | |
dc.contributor.author | Fonseca, Eduardo | |
dc.contributor.author | Kandouz, Mustapha | |
dc.contributor.author | Caeiro, José Ramón | |
dc.contributor.author | Blanco, Alfonso | |
dc.contributor.author | Mayan, Maria D. | |
dc.date.accessioned | 2019-05-27T16:50:21Z | |
dc.date.available | 2019-05-27T16:50:21Z | |
dc.date.issued | 2018-12-05 | |
dc.identifier.citation | VARELA-EIRÍN, Marta, et al. Targeting of chondrocyte plasticity via connexin43 modulation attenuates cellular senescence and fosters a pro-regenerative environment in osteoarthritis. Cell death & disease, 2018, vol. 9, no 12, p. 1166. | es_ES |
dc.identifier.issn | 2041-4889 | |
dc.identifier.uri | http://hdl.handle.net/2183/23017 | |
dc.description.abstract | [Abstract] Osteoarthritis (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. | es_ES |
dc.description.sponsorship | Ministerio de Economía y Competitividad; PRECIPITA-2015-000139 | es_ES |
dc.description.sponsorship | Instituto de Salud Carlos III; PI16/00035 | es_ES |
dc.description.sponsorship | Xunta de Galicia; IN607B 2017/21 | es_ES |
dc.description.sponsorship | Instituto de Salud Carlos III; PI16/00772 | es_ES |
dc.description.sponsorship | Instituto de Salud Carlos III; CPII16/00042 | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Nature Publishing Group | es_ES |
dc.relation.uri | https://doi.org/10.1038/s41419-018-1225-2 | es_ES |
dc.rights | Atribución 3.0 España | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | * |
dc.subject | Connexin43 | es_ES |
dc.subject | Osteoarthritis | es_ES |
dc.subject | Chodrocity plasticity | es_ES |
dc.subject | Cartilage regeneration | es_ES |
dc.title | Targeting of chondrocyte plasticity via connexin43 modulation attenuates cellular senescence and fosters a pro-regenerative environment in osteoarthritis | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.access | info:eu-repo/semantics/openAccess | es_ES |
UDC.journalTitle | Cell Death & Disease | es_ES |
UDC.volume | 9 | es_ES |
UDC.startPage | 1166 | es_ES |
dc.identifier.doi | 10.1038/s41419-018-1225-2 |
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