Early targeting of the YAP/TEAD-PKC-NF-κB axis alleviates post-traumatic osteoarthritis

Post-traumatic osteoarthritis (PTOA) is a progressive joint disease driven by mechanical injury, inflammation, and cartilage degradation. The Hippo signaling effector YAP, acting through an atypicalPKC (aPKC)-NF-κB axis, couples mechanical stress to inflammatory signaling in chondrocytes. Using a murine anterior cruciate ligament (ACL) rupture model, we show that joint injury rapidly co-activates YAP and NF-κB p65 and elicits a staged transcriptional response, from early inflammatory and YAP-associated transcription programs to matrix remodeling. Pharmacologic disruption of Hippo signaling or inhibition of YAP-mediated gene transcription, by preventing YAP from interacting with its transcription partner TEAD, reduced cartilage degeneration and overall joint pathology and reversed injury-induced inflammatory and remodeling programs. These findings provide preclinical proof-of-concept that early pharmacologic intervention can alter the course of PTOA. The ongoing clinical development of TEAD-targeted agents in oncology will facilitate translation of this therapeutic strategy to joint disease.