Targeting of chondrocyte plasticity via connexin43 modulation attenuates cellular senescence and fosters a pro-regenerative environment in osteoarthritis

• Published in: Cell death & disease Vol. 9; no. 12; pp. 1166 - 16
• Main Authors: 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, José Ramón, Blanco, Alfonso, Mayán, María D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.12.2018; Springer Nature B.V
• Subjects: 13/100; 13/106; 13/109; 13/21; 13/31; 13/51; 14/34; 38/77; 692/308/575; 692/699/1670/407; 82/29; 96/63; Antibodies; Arthritis; Biochemistry; Biomedical and Life Sciences; Cartilage (articular); Cartilage diseases; Cell Biology; Cell Culture; Cell signaling; Chondrocytes; Connexin 43; CRISPR; Degeneration; Gap junctions; IL-1β; Immunology; Inflammation; INK4a protein; Knee; Life Sciences; Mesenchyme; NF-κB protein; Nuclear transport; Osteoarthritis; p16 Protein; p53 Protein; Pain; Patients; Phenotypes; Senescence; Signal transduction; Therapeutic applications; Wound healing
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-018-1225-2

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.