Targeting of chondrocyte plasticity via connexin43 modulation attenuates cellular senescence and fosters a pro-regenerative environment in osteoarthritis
Title: | Targeting of chondrocyte plasticity via connexin43 modulation attenuates cellular senescence and fosters a pro-regenerative environment in osteoarthritis
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Author: | Varela Eirín, Marta
Varela Vázquez, Adrián
Guitián Caamaño, Amanda
Paíno, Carlos Luis
Mato, Virginia
Largo, Raquel
Aasen, Trond
Tabernero, Arantxa
Fonseca, Eduardo
Kandouz, Mustapha
Caeiro Rey, José Ramón
Blanco, Alfonso
Mayán, María D.
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Affiliation: | Universidade de Santiago de Compostela. Departamento de Cirurxía e Especialidades Médico-Cirúrxicas
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Date of Issue: | 2018
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Publisher: | Nature Publishing Group
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Citation: | Varela-Eirín, M., Varela-Vázquez, A., Guitián-Caamaño, A. et al. Targeting of chondrocyte plasticity via connexin43 modulation attenuates cellular senescence and fosters a pro-regenerative environment in osteoarthritis. Cell Death Dis 9, 1166 (2018). https://doi.org/10.1038/s41419-018-1225-2
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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. |
Publisher version: | https://doi.org/10.1038/s41419-018-1225-2 |
URI: | http://hdl.handle.net/10347/22936
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DOI: | 10.1038/s41419-018-1225-2 |
E-ISSN: | 2041-4889
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Rights: | © The Author(s) 2018. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
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