Targeting of chondrocyte plasticity via connexin43 modulation attenuates cellular senescence and fosters a pro-regenerative environment in osteoarthritis
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| Main Authors: | , , , , , , , , , , , , |
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| Format: | Preprint |
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2024
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| author | Varela-Eirin, Marta Varela-Vazquez, Adrian Guitian-Caamano, Amanda Paino, Carlos Luis Mato, Virginia Largo, Raquel Aasen, Trond Tabernero, Arantxa Fonseca, Eduardo Kandouz, Mustapha Caeiro, Jose Ramon Blanco, Alfonso Mayan, Maria D. |
| author_facet | Varela-Eirin, Marta Varela-Vazquez, Adrian Guitian-Caamano, Amanda Paino, Carlos Luis Mato, Virginia Largo, Raquel Aasen, Trond Tabernero, Arantxa Fonseca, Eduardo Kandouz, Mustapha Caeiro, Jose Ramon Blanco, Alfonso Mayan, Maria D. |
| contents | 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. 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. |
| format | Preprint |
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arxiv_https___arxiv_org_abs_2402_00624 |
| institution | arXiv |
| publishDate | 2024 |
| record_format | arxiv |
| spellingShingle | Targeting of chondrocyte plasticity via connexin43 modulation attenuates cellular senescence and fosters a pro-regenerative environment in osteoarthritis Varela-Eirin, Marta Varela-Vazquez, Adrian Guitian-Caamano, Amanda Paino, Carlos Luis Mato, Virginia Largo, Raquel Aasen, Trond Tabernero, Arantxa Fonseca, Eduardo Kandouz, Mustapha Caeiro, Jose Ramon Blanco, Alfonso Mayan, Maria D. Tissues and Organs 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. 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. |
| title | Targeting of chondrocyte plasticity via connexin43 modulation attenuates cellular senescence and fosters a pro-regenerative environment in osteoarthritis |
| topic | Tissues and Organs |
| url | https://arxiv.org/abs/2402.00624 |