A Novel EphA4 Based Small Molecule Based Therapeutic Strategy for Prevention and Treatment of Post Traumatic Osteoarthritis

Post-traumatic osteoarthritis (PTOA) is a painful and debilitating disease of the joints, characterized by intra-articular inflammation, deterioration of articular cartilage, and degenerative changes to peri-articular and subchondral bone. There is currently no effective therapy. This project capitalizes our discovery that the forward signaling of EphA4 receptor has both an anti-catabolic effect (on osteoclasts/chondroclasts) and an anabolic effect (on chondrocytes) on skeletal tissues and seeks to develop a small molecule-based therapy for PTOA that involves merely direct injection of a soluble EphA4-acting EfnA-fc protein into the injured synovium. We will first confirm that EfnA-fc-mediated activation of the forward signaling of EphA4 in synoviocytes and infiltrating neutrophils/monocytes would reduce survival and the release of pro-inflammatory cytokines and MMPs, but, in articular chondrocytes, would enhance chondrogenesis in vitro. We will then optimize a small molecule EfnA-fc-based strategy involving injections of an EphA4-binding EfnA-fc into the joint by determining an appropriate EfnA-fc ligand for EphA4, an optimal dosage, and the time course of the effect, and an appropriate duration between injections. Finally, we will determine whether the small molecule EfnA-fc-based therapeutic strategy can prevent PTOA-mediated degradation of articular cartilage in early PTOA, and also can promote regeneration of articular cartilage in established PTOA. If this therapy is effective, it will improve the quality of life of PTOA patients, not only in the active duty military personnel and the veteran population, but also in the civilian population. It may even allow the warrior to return to active duty. This proposal has high military benefits. 01 Jan 0001, 01 Jan 0001, Revised Annual Report