ISSN: 2161-1149 (Printed)
Scientific Tracks Abstracts: Rheumatology & Orthopedics
O steoarthritis (OA) is the most common form of joint disease in middle-aged and older populations. Currently, no proven disease-modifying pharmacologic therapy is available largely because the pathogenetic mechanisms of OA remain unclear. Previous studies suggest that overexpression of matrix-degrading proteinases and proinflammatory cytokines may contribute to articular cartilage degradation. However, it remains unclear which transcription factors regulate the expression of these cartilage- degrading molecules in articular cartilage. Our recent studies discovered that mice lacking Nfat1, a member of the nuclear factor of activated T-cells (NFAT/Nfat) transcription factors, exhibited normal skeletal development but displayed characteristics of human OA as adults. Adult Nfat1-deficient mice showed articular cartilage degradation with overexpression of specific matrix- degrading proteinases and proinflammatory cytokines. Pathologic chondrocyte differentiation was observed in the synovium adjacent to the joint margins, followed by chondro-osteophyte formation through endochondral ossification. Abnormal chondrocyte differentiation and endochondral ossification also occurred in the subchondral bone marrow, leading to thickening of the subchondral bone. These new findings revealed a previously unrecognized role of Nfat1 in maintaining the physiological function of adult joint tissue cells. Nfat1 deficiency causes OA due to an imbalance between catabolic and anabolic activities of adult articular chondrocytes as well as pathologic differentiation of mesenchymal progenitor cells in other joint tissues, leading to cartilage and bone changes in the affected joints. Because Nfat1 regulates the expression of multiple catabolic and anabolic molecules in articular tissues, anti-OA agents that target Nfat1 could be more effective than drug candidates that target a single catabolic/anabolic molecule.
Dr. Jinxi Wang is the Harrington Distinguished Professor of Orthopedics and Director of the Harrington Laboratory for Molecular Orthopedics at the University of Kansas Medical Center. His major research interests are: (1) molecular regulation of chondrocyte function and articular cartilage regeneration, (2) pathogenetic mechanisms and novel therapeutics for osteoarthritis, and (3) regulatory mechanisms of osteoblast differentiation and bone regeneration. He is an editorial board member and manuscript reviewer for several biomedical and orthopedic research journals. He also serves as a reviewer of grant applications for the National Institutes of Health (NIH, USA) and other national and international research funding agencies