Calcineurin and NFAT4 Induce Chondrogenesis

• Published in: The Journal of biological chemistry Vol. 277; no. 44; pp. 42214 - 42218
• Main Authors: Tomita, Masuhiro, Reinhold, Martina I, Molkentin, Jeffery D, Naski, Michael C
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 01.11.2002
• Subjects: Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins - biosynthesis; Bone Morphogenetic Proteins - genetics; Calcineurin - physiology; Cell Differentiation - drug effects; Cells, Cultured; Chondrogenesis; DNA-Binding Proteins - physiology; Gene Expression Regulation - drug effects; Ionomycin - pharmacology; Mice; NFATC Transcription Factors; Nuclear Proteins; Transcription Factors - physiology; Transforming Growth Factor beta
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.C200504200

Nuclear factor of activated T-cells (NFAT) and calcineurin are essential regulators of immune cell and mesenchymal cell differentiation. Here we show that elevated intracellular calcium induces chondrogenesis through a calcineurin/NFAT signaling axis that activates bone morphogenetic protein (BMP) expression. The calcium ionophore, ionomycin, induced chondrogenesis through activation of calcineurin. The calcineurin substrate, NFAT4, also induced chondrogenesis and chondrocyte gene expression. Significantly, the BMP antagonist, noggin, or dominant negative BMP receptors blocked the effects of elevated intracellular calcium on chondrogenesis. This suggested that calcineurin/NFAT4 activates BMP expression. Consistent with this, BMP2 gene expression was increased by ionomycin and suppressed by the calcineurin inhibitor, cyclosporine A. Furthermore, activated NFAT4 induced BMP2 gene expression. These results have important implications for the effects of NFATs during development and adaptive responses.