| Autor: |
Hallström GF; McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine.; Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA 19104.; Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA 19104., Jones DL; McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine., Locke RC; McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine.; Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA 19104.; Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA 19104., Bonnevie ED; McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine.; Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA 19104.; Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA 19104., Kim SY; McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine.; Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA 19104.; Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104.; Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA 19104., Laforest L; McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine., Garcia DC; McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine., Mauck RL; McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine.; Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA 19104.; Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104.; Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA 19104. |
| Abstrakt: |
Chondrocyte phenotype is preserved when cells are round and the 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 mechanism is not yet fully elucidated. Yap, a transcriptional coregulator, is regulated by Rho in a mechanotransductive manner and can suppress chondrogenesis in vivo. Here, we sought to elucidate the relationship between mechanoactive Rho and Yap on chondrogenic gene expression. We first show that decreasing mechanoactive state through Rho inhibition results in a broad increase in chondrogenic gene expression. Next, we show that Yap and its coregulator Taz are negative regulators of chondrogenic gene expression, and removal of these factors promotes chondrogenesis even in environments that promote cell spreading. Finally, we establish 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. |
