YAP activation inhibits inflammatory signalling and cartilage breakdown associated with reduced primary cilia expression

To clarify the role of YAP in modulating cartilage inflammation and degradation and the involvement of primary cilia and associated intraflagellar transport (IFT).Isolated primary chondrocytes were cultured on substrates of different stiffness (6-1000 kPa) or treated with YAP agonist lysophosphatidic acid (LPA) or YAP antagonist verteporfin (VP), or genetically modified by YAP siRNA, all ± IL1β. Nitric oxide (NO) and prostaglandin ETreatment with LPA, or increasing polydimethylsiloxane (PDMS) substrate stiffness, activated YAP nuclear expression and inhibited IL1β-induced release of NO and PGEWe demonstrate that both pharmaceutical and mechanical activation of YAP blocks pro-inflammatory signalling induced by IL1β and prevents cartilage breakdown and the loss of biomechanical functionality. This is associated with reduced expression of primary cilia revealing a potential anti-inflammatory mechanism with novel therapeutic targets for treatment of osteoarthritis (OA).