Osteoarthritis (OA), in particular, post-traumatic osteoarthritis (PTOA) is highly prevalent in U.S. military service members and veterans due to the impact of joint trauma and overuse injury. Its socioeconomic impact is substantial, estimated to approach $60 billion per year, and no disease-modifying treatments exist. Current understanding is that PTOA is caused by maladaptive repair responses including activation of the pro- inflammatory pathways of innate immunity that in turn result in pain, loss of function and structural decline. This project addresses the hypothesis that promotion of hyaline cartilage repair will effectively alter the course of PTOA, relieve joint pain and improve joint function. Native mesenchymal stem cells (MSC) residing in the joint are important targets for manipulation to differentiate into chondrocytes. These joint-resident MSCs include cartilage progenitor cells, MSCs in synovial fluid, synovium and adipose tissue. SOX9 (SRY-type high-mobility group box gene-9) is the master transcription factor for chondrogenesis of MSCs. We have produced a superpositively charged SOX9 (scSOX9) which can penetrate into MSCs and induce chondrogenesis. We have demonstrated in an acute cartilage injury model that scSOX9 induced hyaline-like cartilage repair by promoting chondrogenesis of bone marrow derived MSCs (BM-MSCs). By using medial meniscal transection (MMT) induced rat PTOA model, we will test the therapeutic effect of scSOX9 by harnessing the chondrogenic potential of these joint-resident MSCs for regeneration of hyaline cartilage. Pain and joint function will be assessed clinically in live animals by measuring behavior changes at different time points of the disease course. The degree of cartilage regeneration or repair and synovitis will be quantified by advanced imaging system. At the termination of experiments, the biomechanical property of the repaired cartilage will be measured on intact cartilage with subchondral bone using biomomentum indentation technology. Cartilage degradation, repair and synovitis will also be determined by standardized methods of histopathology and immunohistochemistry.