Osteoarthritis (OA) is the most common form of joint disease and the major cause of chronic disability in middle-aged and older populations. Although multiple risk factors, including mechanical abnormalities, aging, joint injuries, and genetic predisposition, have been proposed to be involved in the pathogenesis of OA, no proven structure-modifying pharmacologic therapy is currently available to prevent the initiation of OA or reverse the progression of the disease. Overexpression of catabolic cartilage-degrading proteinases and proinflammatory cytokines has been shown to cause articular cartilage degradation. However, key upstream biological factors that regulate the expression of these catabolic molecules remain unclear. We have recently found that mice lacking Nfat1, a member of the nuclear factor of activated T-cells (NFAT) transcription factors, exhibit normal skeletal development but display OA-like changes with overexpression of catabolic proteinases and cytokines in affected articular cartilage of adult animals. The molecular mechanisms for NFAT1 deficiency- associated OA remain unclear. The objective of this application is to explore the molecular and cellular mechanisms underlying the pathogenesis of Nfat1 deficiency-induced OA in mice. Our central hypothesis is that NFAT1 is a key factor for maintenance of the function of adult articular chondrocytes and mesenchymal progenitor cells in the joint tissues, and that NFAT1 deficiency causes OA through dysfunction of adult articular chondrocytes and pathological differentiation of progenitor cells in the joint. This hypothesis will be tested through the following specific aims: (1) investigate the mechanisms of age-dependent OA phenotype in Nfat1- deficient mice, (2) determine Nfat1 target genes in joint tissue cells, and (3) determine which joint tissue(s) is primarily affected by NFAT1 deficiency. Successful completion of these proposed studies may direct us to develop innovative and effective strategies for the prevention and treatment of OA.

Public Health Relevance

The major goal of this project is to explore the molecular and cellular mechanisms by which transcription factor NFAT1 deficiency causes osteoarthritic joint degeneration. Successful completion of the proposed studies may provide new insights into the etiopathogenesis of osteoarthritis and could lead to improved strategies for prevention and treatment of osteoarthritis.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Biology Structure and Regeneration Study Section (SBSR)
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Tyree, Bernadette
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University of Kansas
Schools of Medicine
Kansas City
United States
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Zhang, Mingcai; Lygrisse, Kate; Wang, Jinxi (2017) Role of MicroRNA in Osteoarthritis. J Arthritis 6:
Zhang, M; Lu, Q; Egan, B et al. (2016) Epigenetically mediated spontaneous reduction of NFAT1 expression causes imbalanced metabolic activities of articular chondrocytes in aged mice. Osteoarthritis Cartilage 24:1274-83
Feng, Yi; Egan, Brian; Wang, Jinxi (2016) Genetic Factors in Intervertebral Disc Degeneration. Genes Dis 3:178-185
Zhang, Mingcai; Lu, Qinghua; Miller, Andrew H et al. (2016) Dynamic epigenetic mechanisms regulate age-dependent SOX9 expression in mouse articular cartilage. Int J Biochem Cell Biol 72:125-134
Blalock, Darryl; Miller, Andrew; Tilley, Michael et al. (2015) Joint instability and osteoarthritis. Clin Med Insights Arthritis Musculoskelet Disord 8:15-23
Zhang, Mingcai; Egan, Brian; Wang, Jinxi (2015) Epigenetic mechanisms underlying the aberrant catabolic and anabolic activities of osteoarthritic chondrocytes. Int J Biochem Cell Biol 67:101-9
Zhang, Mingcai; Wang, Jinxi (2015) Epigenetics and Osteoarthritis. Genes Dis 2:69-75
Caldwell, K L; Wang, J (2015) Cell-based articular cartilage repair: the link between development and regeneration. Osteoarthritis Cartilage 23:351-62
Kramer, William C; Hendricks, Kelly J; Wang, Jinxi (2011) Pathogenetic mechanisms of posttraumatic osteoarthritis: opportunities for early intervention. Int J Clin Exp Med 4:285-98
Rodova, Marianna; Lu, Qinghua; Li, Ye et al. (2011) Nfat1 regulates adult articular chondrocyte function through its age-dependent expression mediated by epigenetic histone methylation. J Bone Miner Res 26:1974-86