(Taken from the application): NFAT transcription factors regulate gene expression in lymphocytes, control cardiac valve formation and affect muscle cell differentiation. We have recently discovered that one member of this family, NFATp, regulates cartilage cell differentiation in the adult animal. In mice lacking NFATp, resident cells in the extra-articular connective tissues spontaneously differentiate to cartilage. This cartilage subsequently undergoes endochondral ossification, recapitulating the development of endochondral bone. Proliferation of articular cartilage cells also occurs in some older animals. Consistent with these data, NFATp expression is regulated in mesenchymal stem cells induced to differentiate along a chondrogenic pathway while over expression of NFATp in cartilage cell lines represses the cartilage phenotype. Few molecular regulators of chondrogenesis are known, and most of these operate during skeletal morphogenesis rather than in the adult animal. Our studies demonstrate that a member of the NFAT family of transcription factors, NFATp, is a repressor of cartilage cell growth and differentiation in the adult animal. Compounds that block the function of NFATp in cartilage may prove valuable in achieving sustained differentiation and growth of cartilage from mesenchymal stem cells in vitro or in vivo. Such inhibitors might control mesenchymal stem cell recruitment and chondrogenesis in response to environmental injuries such as occur during normal mechanical wear and tear. The potential use of such NFATp inhibitors in degenerative joint diseases such as osteoarthritis or inflammatory arthritis or in repair of endochondral bone defects and fractures, where cartilage and/or bone has been destroyed, is obvious. The mechanism by which NFATp controls chondrogenesis is unknown. In this application we wish to explore our initial discovery in the following ways. We propose to 1) further investigate the role of NFAT proteins in vivo by the creation of conditional knockout mice and cell lines, 2) to identify the function of NFATp in mesenchymal progenitor cells and mature cartilage cells by identifying NFATp target genes and interacting proteins in these tissues and 3) to test whether repair of articular cartilage and bone is affected by the presence of NFATp.
