Project Title: Therapeutic Role of NFAT1 Transcription Factor in Osteoarthritis Project Summary Osteoarthritis (OA) is the most prevalent joint disease in middle-aged and older populations. Traditionally, OA is classified into primary (spontaneous/idiopathic) and secondary (induced by joint injury or abnormal joint formation) OA. Since age is the overriding risk factor for OA and loss of articular cartilage (AC) occurs in the load-bearing area of OA joints, OA has long been considered a mechanical issue resulting from the “wear and tear” of AC over time. Recent studies suggest that all the joint tissues may be involved in the disease process, though AC degeneration is the major hallmark of OA. Currently, no pharmacologic therapy is available to halt or reverse the process of joint aging and OA due to unknown regulatory mechanisms underlying the OA changes. NFAT1 is a member of the nuclear factor of activated T cells (NFAT) transcription factor family. Our recent studies showed that mice with a global deletion of the Nfat1 gene (Nfat1-/- mice) displayed normal skeletal formation but manifested OA in adult mice. Lower AC NFAT1 levels correlated with earlier onset and more severe OA changes in Nfat1-deficient mice. Age-related reduction of NFAT1 expression in the joint tissues was also observed in normal mice after 12 months of age, with age-related cell dysfunction. Our preliminary human studies revealed that higher AC NFAT1 levels correlated with less severe radiographic OA grades, and vice versa. The data suggest the protective potential of NFAT1 against OA progression. The objective of this proposal is to investigate the therapeutic role of NFAT1 treatment in joint aging and OA development using OA mouse models and human joint-tissues with primary OA. Specific Aim 1 is to investigate the therapeutic role of AAV-Nfat1 (adeno-associated virus/AAV delivered Nfat1 transgene) in knee OA mouse models. Specific Aim 2 is to determine the therapeutic role of NFAT1 in human cartilage and synovium tissue samples with primary OA. Positive results of this preclinical project will promote the development of a personalized OA therapy in patients with significantly reduced NFAT1 expression or biological activities.