ChondroCONNECT · Development of a connexon-proteoliposome delivery system to ameliorate inflammatory and mechanical stress responses in the regeneration of osteoarthritic cartilage

Development of a connexon-proteoliposome delivery system to ameliorate inflammatory and mechanical stress responses in the regeneration of osteoarthritic cartilage

Degeneration of cartilage at joint surfaces due to injury, age or disease (e.g., osteoarthritis; OA) causes significant pain, disability and decreased quality of life. Current treatments fail to effectively repair cartilage and typically only manage symptoms and delay the degeneration that leads to OA and the need for joint replacement. OA affects over 500 million people worldwide and costs countries in the EU approximately 1-2 % of their Gross Domestic Product. Adult cartilage has a poor capacity to heal, which is limited further by the inflammatory and senescent cell environment present in the degenerative joint. Recent attention has focused on therapies that promote cartilage regeneration and simultaneously target key inflammatory mediators to inhibit their effect. This approach has the potential to break the vicious cycle of cartilage degeneration and allow the tissue to repair sufficiently to restore mechanical functionality. This fellowship focused on one such emerging potential molecular target, connexin-43 (Cx43), a protein that forms channels capable of transporting small molecules across cell membranes. In OA cartilage, Cx43 protein expression is increased approximately 40-fold. The mechanisms of Cx43 upregulation in OA and its role in OA pathology are yet to be fully understood but both channel and non-channel Cx43 activities appear to be important regulators of cell behaviour. Increased Cx43 expression has been linked to increased spreading of pro-inflammatory signalling in OA, while non-channel Cx43 activity may be involved in transcriptional regulation of cartilage-relevant genes like N-cadherin and Twist1. The above findings point towards an important role for a Cx43-sensitive signalling axis in cartilage cell (chondrocyte) responses to proinflammatory cytokines and adoption of OA-like cell phenotypes. Therefore, during this project, I aimed to investigate the role of Cx43 in chondrocyte responses to proinflammatory stimuli associated with OA at various levels, including gene expression, metabolic regulation, and channel and non-channel activity. I then aimed to identify key processes in these responses, and develop and test an siRNA-based therapeutic for the regeneration of cartilage tissue in a three-dimensional culture environment.

Data: CORDIS, © European Union