Rachel Matz-Westphal - Academia.edu (original) (raw)
Papers by Rachel Matz-Westphal
Osteoarthritis (OA) is the most prevalent joint disease. The hallmark of this pathology is the gr... more Osteoarthritis (OA) is the most prevalent joint disease. The hallmark of this pathology is the gradual loss of articular cartilage (AC), composed of a single cell type, the chondrocyte. Chondrocytes synthesize an abundant extracellular matrix (ECM) that mainly consists of type II collagen (Col II) and aggrecan. During OA development, stable chondrocytes undergo hypertrophic maturation leading to the synthesis of type X Collagen (Col X) along with enzymes that degrade the ECM, resulting in the decreased production of Col II, the mineralization of the matrix and subsequent ossification of the cartilage. To directly test the role of ShcA (Src Homology and Collagen A) in chondrocyte differentiation in vivo, our lab generated conditional mice lacking ShcA in chondrocytes using the Cre-lox system (Twist 2 ShcA KO). Mice that lack ShcA, exhibit a dwarfism phenotype, associated with a diminished bone-to-cartilage ratio, and a disorganized growth plate with a decreased hypertrophic maturation of chondrocytes indicating a crucial need for ShcA in the terminal chondrogenic hypertrophy process. In addition, tibio-femoral sections analysis showed that these mice exhibit larger proteoglycan and Col II and less col X expression and are protected from severe age-related OA development. These results were further validated in-vitro by using dedifferentiated chondrocytes that underwent either chondrogenic or hypertrophic differentiation in collagen structures later implanted in nude mice (collaboration with A. Barbero). We observed that ShcA-/-cells showed increased expression of stable cartilage markers and a decrease in the expression of hypertrophy markers accompanied by a reduced metalloproteinase activity. Furthermore, ShcA-/-cells showed a diminished activation of the MAPK pathway and subsequent decrease in the activation of RunX2, a master transcription factor for chondrocyte hypertrophy, along with a significantly reduced ColX mRNA stability. We have also uncovered a novel mechanism by which ShcA controls the activity of the Hippo pathway effector YAP1 in hypertrophic conditions. An advanced understanding of the exact role of ShcA has the potential to identify the gene as a therapeutic target. Also, chondro-induced ShcA-deleted mesenchymal stem cells could be useful to engineer a stable cartilage tissue for proper cartilage matrix regeneration in-vivo and to bring the possibility of using this novel approach to a pre-clinical level.
Journal of Biological Chemistry, 2004
The third member of the family of junctional adhesion molecules (JAMs), JAM-3, also called JAM-C,... more The third member of the family of junctional adhesion molecules (JAMs), JAM-3, also called JAM-C, was recently shown to be a novel counter-receptor on platelets for the leukocyte  2-integrin Mac-1 (␣M 2 , CD11b/CD18). Here, new functional aspects of the role of endothelial cell JAM-C were investigated. Endothelial cells express JAM-C, which is predominantly localized within junctions at interendothelial contacts, since it codistributes with a tight junction component, zonula occludens-1. Whereas JAM-C does not participate in neutrophil adhesion to endothelial cells, it mediates neutrophil transmigration in a Mac-1-dependent manner. In particular, inhibition of JAM-C significantly reduced neutrophil transendothelial migration, and the combination of JAM-C and platelet/endothelial cell adhesion molecule-1 blockade almost completely abolished neutrophil transendothelial migration in vitro. In vivo, inhibition of JAM-C with soluble mouse JAM-C resulted in a 50% reduction of neutrophil emigration in the mouse model of acute thioglycollate-induced peritonitis. Thus, JAM-C participates in neutrophil transmigration and thereby provides a novel molecular target for antagonizing interactions between vascular cells that promote inflammatory vascular pathologies.
Osteoarthritis (OA) is the most prevalent joint disease. The hallmark of this pathology is the gr... more Osteoarthritis (OA) is the most prevalent joint disease. The hallmark of this pathology is the gradual loss of articular cartilage (AC), composed of a single cell type, the chondrocyte. Chondrocytes synthesize an abundant extracellular matrix (ECM) that mainly consists of type II collagen (Col II) and aggrecan. During OA development, stable chondrocytes undergo hypertrophic maturation leading to the synthesis of type X Collagen (Col X) along with enzymes that degrade the ECM, resulting in the decreased production of Col II, the mineralization of the matrix and subsequent ossification of the cartilage. To directly test the role of ShcA (Src Homology and Collagen A) in chondrocyte differentiation in vivo, our lab generated conditional mice lacking ShcA in chondrocytes using the Cre-lox system (Twist 2 ShcA KO). Mice that lack ShcA, exhibit a dwarfism phenotype, associated with a diminished bone-to-cartilage ratio, and a disorganized growth plate with a decreased hypertrophic maturation of chondrocytes indicating a crucial need for ShcA in the terminal chondrogenic hypertrophy process. In addition, tibio-femoral sections analysis showed that these mice exhibit larger proteoglycan and Col II and less col X expression and are protected from severe age-related OA development. These results were further validated in-vitro by using dedifferentiated chondrocytes that underwent either chondrogenic or hypertrophic differentiation in collagen structures later implanted in nude mice (collaboration with A. Barbero). We observed that ShcA-/-cells showed increased expression of stable cartilage markers and a decrease in the expression of hypertrophy markers accompanied by a reduced metalloproteinase activity. Furthermore, ShcA-/-cells showed a diminished activation of the MAPK pathway and subsequent decrease in the activation of RunX2, a master transcription factor for chondrocyte hypertrophy, along with a significantly reduced ColX mRNA stability. We have also uncovered a novel mechanism by which ShcA controls the activity of the Hippo pathway effector YAP1 in hypertrophic conditions. An advanced understanding of the exact role of ShcA has the potential to identify the gene as a therapeutic target. Also, chondro-induced ShcA-deleted mesenchymal stem cells could be useful to engineer a stable cartilage tissue for proper cartilage matrix regeneration in-vivo and to bring the possibility of using this novel approach to a pre-clinical level.
Journal of Biological Chemistry, 2004
The third member of the family of junctional adhesion molecules (JAMs), JAM-3, also called JAM-C,... more The third member of the family of junctional adhesion molecules (JAMs), JAM-3, also called JAM-C, was recently shown to be a novel counter-receptor on platelets for the leukocyte  2-integrin Mac-1 (␣M 2 , CD11b/CD18). Here, new functional aspects of the role of endothelial cell JAM-C were investigated. Endothelial cells express JAM-C, which is predominantly localized within junctions at interendothelial contacts, since it codistributes with a tight junction component, zonula occludens-1. Whereas JAM-C does not participate in neutrophil adhesion to endothelial cells, it mediates neutrophil transmigration in a Mac-1-dependent manner. In particular, inhibition of JAM-C significantly reduced neutrophil transendothelial migration, and the combination of JAM-C and platelet/endothelial cell adhesion molecule-1 blockade almost completely abolished neutrophil transendothelial migration in vitro. In vivo, inhibition of JAM-C with soluble mouse JAM-C resulted in a 50% reduction of neutrophil emigration in the mouse model of acute thioglycollate-induced peritonitis. Thus, JAM-C participates in neutrophil transmigration and thereby provides a novel molecular target for antagonizing interactions between vascular cells that promote inflammatory vascular pathologies.