Targeting of chondrocyte plasticity via connexin43 modulation attenuates cellular senescence and fosters a pro-regenerative environment in osteoarthritis
Varela-Eirín, Marta (Universidade da Coruña)
Varela-Vázquez, Adrián (Universidade da Coruña)
Guitián-Caamaño, Amanda
Paíno, Carlos Luis (Instituto Ramón y Cajal de Investigación Sanitaria (Madrid))
Mato, Virginia (Universidade da Coruña)
Largo, Raquel (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)
Aasen, Trond (Hospital Universitari Vall d'Hebron)
Tabernero, Arantxa (Universidad de Salamanca)
Fonseca, Eduardo (Universidade da Coruña)
Kandouz, Mustapha (Wayne State University. Department of Pathology, School of Medicine)
Caeiro Rey, José Ramón (Complejo Hospitalario Universitario de Santiago de Compostela)
Blanco, Alfonso (University College Dublin C). CellCOM research)
Mayán, María D. (Universidade da Coruña)
Universitat Autònoma de Barcelona

Data:	2018
Resum:	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, p16 INK4a 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.
Ajuts:	Ministerio de Economía y Competitividad PI13/00763 Ministerio de Economía y Competitividad PI16/00772 Ministerio de Economía y Competitividad CPII16/00042
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Cell death and disease, Vol. 9 (december 2018) , ISSN 2041-4889

DOI: 10.1038/s41419-018-1225-2
PMID: 30518918

16 p, 2.1 MB

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