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.
Highlights
Osteoarthritis (OA), a chronic disorder characterized by the progressive degradation of articular cartilage, is the most prevalent and disabling musculoskeletal disease worldwide[1,2]
osteoarthritic chondrocytes (OACs) acquire a stem-like phenotype To test whether immature chondrocytes contribute to OA pathogenesis, we first asked whether chondrocytes isolated from OA patients express stemness-associated cell surface markers (Fig. 1)
We demonstrate that the gap junctions (GJs) channel protein Cx43 acts as a positive regulator that reverts chondrocytes to a less differentiated state, possibly by upregulating the activity of factors such as the basic helix-loop-helix transcription factor Twist-1 (Fig. 3) and inflammatory cytokines such as IL-1β (Fig. 4)
Summary
Osteoarthritis (OA), a chronic disorder characterized by the progressive degradation of articular cartilage, is the most prevalent and disabling musculoskeletal disease worldwide[1,2]. Osteoarthritic cartilage exhibits changes in its extracellular matrix (ECM) composition caused by alterations in component synthesis and degradation[3,4]. In the early stages of OA, osteoarthritic chondrocytes (OACs) undergo phenotypic changes that increase cell proliferation and cluster formation, with enhanced expression of matrix-remodelling enzymes reflecting attempts to repair the damage. Disruption of the pericellular matrix and progressive cartilage degradation together with changes in subchondral bone, synovial and other joint tissues are characteristic features of disease progression that are associated with increased pain and physical disability[5,6]. Cell dedifferentiation and reprogramming are associated with wound healing and tissue regeneration[16,17,18] Biological conditions such as tissue injury and ageing promote a precise spatiotemporal cellular plasticity and in vivo reprogramming to achieve tissue repair[19]. Changes in cell plasticity can cause pathological processes, such as fibrosis and tumour progression[20,21,22,23]
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