Targeting F-actin to promote the redifferentiation of chondrocytes
Date
2023
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
University of Delaware
Abstract
Articular cartilage is incapable of self- repair and any damage to the tissue results in degradation leading to Osteoarthritis. To prevent Osteoarthritis progression, cell-based therapies such as autologous chondrocyte implantation are often used. However, monolayer expansion of articular chondrocytes for autologous cell implantation leads to their dedifferentiation. During dedifferentiation there is a reduction in the expression of chondrogenic molecule expression and an increase in expression of fibroblastic and contractile molecule expression. This causes cells to produce biomechanically inferior fibrocartilage that lacks longevity and has the potential for matrix shrinkage resulting in failed integration. The actin cytoskeleton plays a key role in regulating chondrocyte shape and mRNA expression partly through direct regulation by myocardin-related transcription factor. Targeting the actin cytoskeleton may be a means to favorably modulate chondrocyte phenotype for OA therapies. However, how to target specific actin networks remains to be elusive. Tropomyosins and the Rho-GTPases are regulators of the actin cytoskeleton. In this study, I examined the hypothesis that targeting specific filamentous actin (F-actin) regulatory molecules will lead to actin depolymerization and a decrease in the dedifferentiated phenotype. This will provide a molecular target for improving therapeutics to treat cartilage damage. I determined that Tpm 3.1 and Cdc42 inhibition of dedifferentiated, passaged chondrocytes lead to a decrease in fibroblastic (tenascin-c and collagen I) and contractile (α-smooth muscle actin and transgelin) as well as an increase in chondrogenic molecule Sox9. This is supported via the cytoplasmic localization of myocardin-related transcription factor. These provide a potential molecular target to improve the longevity of cell-based regenerative therapies.
Description
Keywords
Osteoarthritis progression, Autologous cell, Cytoskeleton, Depolymerization, Molecule expression