MICROENVIRONMENTAL MECHANOACTIVATION THROUGH YAP/TAZ SUPPRESSES CHONDROGENIC GENE EXPRESSION
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The phenotype of chondrocytes, the primary cells found in articular cartilage, is preserved when they round and their actin cytoskeleton is cortical. Conversely, these cells rapidly dedifferentiate in vitro with increased mechanoactive Rho signaling, which increases cell size and causes large actin stress fiber to form. While the effects of Rho on chondrocyte phenotype are well established, the molecular mechanisms by which this occurs have not been fully elucidated. Yap, a transcriptional co-regulator, is regulated by Rho in a mechanotransductive manner and can suppress chondrogenesis in vivo. In this thesis, we sought to elucidate the relationship between mechanoactive Rho and Yap signaling on chondrogenic gene expression. After establishing an optimized in vitro system to study chondrogenesis, we first showed that decreasing mechanoactive state through Rho inhibition resulted in a broad increase in chondrogenic gene expression. Next, we showed that Yap and its co-regulator Taz, are negative regulators of chondrogenic gene expression, and that removal of these factors promoted chondrogenesis, even in stiff microenvironments that result in cell spreading. Finally, we established that Yap/Taz is essential for translating Rho-mediated signals to negatively regulate chondrogenic gene expression, and that its removal negates the effects of increased Rho signaling. Together, these data indicate that Rho is a mechanoregulator of chondrogenic differentiation, and that its impact on chondrogenic expression is exerted principally through mechanically-induced translocation and activity of Yap and Taz. This thesis closes with a discussion of future avenues to define the precise location and means by which Yap exerts this effect, as well ways to leverage this new knowledge toward therapeutic applications that can improve cartilage repair outcomes.
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Gadue, Paul