Role of connexin43 in cell plasticity and tissue degeneration in osteoarthritis

Abstract

Osteoarthritis (OA) is a chronic disease and a leading cause of disability and pain worldwide, characterized by articular cartilage degradation and joint degeneration. OA chondrocytes (OAc) undergo phenotypic changes and senescence, restricting cartilage regeneration and favouring disease progression. Similar to other wound-healing disorders, OAc show a chronic increase in the transmembrane channel protein connexin43 (Cx43), which regulates signal transduction through the exchange of elements or recruitment/release of signalling factors. The results of this study demonstrated that Cx43 acts as a positive regulator of human chondrocyte reversion to a less differentiated state. Overactive Cx43 maintains this immature phenotype by increasing the nuclear translocation of Twist-1 and increasing the expression of tissue remodelling and proinflammatory agents, such as MMPs and IL-1β, which finally results in cellular senescence through upregulation of p53/p16INK4a and NF-κB, contributing to the senescence-associated secretory phenotype (SASP). In addition, Cx43 can modify the content of the extracellular vesicles probably by facilitating the binding of proteins and molecules of RNA and DNA involved in different signalling routes. The results indicate that the deliver of this content seems to control cellular plasticity in nearby and distant cells. However, downregulation of Cx43 (in chondrocytes and EVs), using the small molecule oleuropein or a mimetic peptide, led to rediferentiation of OAc into a more differentiated state, associated with decreased production of MMPs and expression of proinflammatory factors, such as IL-1ß. This effect results in a reduction in cellular senescence. Collectively, these results identify a causal Cx43-sensitive circuit in chondrocytes that regulates dedifferentiation/redifferentiation and senescence, events critical to wound healing and tissue regeneration. Targeting Cx43 allows immature chondrocytes to revert to a chondrocyte-specific phenotype and its subsequent recovery in a predictable manner. These findings support the use of Cx43 as an appropriate therapeutic target to halt OA progression and to promote cartilage regeneration.