Joint trauma and subsequent osteoarthritis (OA) remain significant injuries in racehorses and the aging human population. Arthritis is second only to tendon and ligament injury as the leading cause of racehorse retirement. Moreover, there are no treatments that markedly alter the progression of OA, and most therapies have focused on symptom-modifying treatments, including analgesics and physical therapy, with end-stage disease typically resulting in arthrodesis or joint replacement, and often concurrent retirement from an athletic career. Lubricin has been investigated as a potential new biotherapeutic that may replace hyaluronic acid (HA) as an injectable for equine joint disease. The aims of the proposed research are to propagate and clone equine lubricin, test its expression in articular cells, combine it with a previously developed attenuated adenovirus expressing interleukin-1 receptor antagonist, and test the combined construct for dual expression and impact in a carpal chip osteoarthritis model. The long-term goal is to prevent the progression of osteoarthritis (OA) through gene- mediated lubricin supplementation combined with suppression of the degradatory and inflammatory master controller, interleukin-1. The broad objectives of this proposal are to develop a dual effector approach to resolution of joint disease in equine athletes. Our previous Zweig grant determined the biophysical organization of lubricin on articular cartilage, the partnering role of the galectins, and the levels and location of lubricin in joint trauma and osteoarthritis. These studies suggest that lubricin protects articular cartilage from fibrillation by functioning as a boundary lubricant and is further concentrated in the damaged surface layer of cartilage in an effort to protect from deeper fibrillation. We hypothesize that the lubricin boundary layer can be enhanced through gene mediated synthesis, and that a combined effect to limit further malacia can be derived by suppressing the principal degradative cytokine, interleukin 1. This treatment paradigm builds on the role of interleukin-1 antagonist protein (IL-1Ra) as the gatekeeper for rampant IL-1 induced matrix catabolism, combined with the fundamental knowledge garnered from biophysical and functional lubricin and galectin studies that show lubricin supplementation can enhance boundary lubrication and limit the impact of osteoarthritis. The hypothesis will be tested by several specific aims.