The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Farshid Guilak - One of the best experts on this subject based on the ideXlab platform.
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type vi collagen regulates pericellular matrix properties chondrocyte swelling and mechanotransduction in mouse articular cartilage
Arthritis & Rheumatism, 2015Co-Authors: Nicole A Zelenski, Holly A. Leddy, Wolfgang Liedtke, Johannah Sanchezadams, Jinzi Zhang, Paolo Bonaldo, Farshid GuilakAbstract:Objective Mechanical factors play a critical role in the physiology and pathology of articular cartilage, although the mechanisms of Mechanical Signal transduction are not fully understood. We undertook this study to test the hypothesis that type VI collagen is necessary for mechanotransduction in articular cartilage by determining the effects of type VI collagen knockout on the activation of the mechano-osmosensitive, calcium-permeable channel TRPV4 (transient receptor potential vanilloid channel 4) as well as on osmotically induced chondrocyte swelling and pericellular matrix (PCM) Mechanical properties. Methods Confocal laser scanning microscopy was used to image TRPV4-mediated calcium Signaling and osmotically induced cell swelling in intact femora from 2- and 9-month-old wild-type (WT) and type VI collagen–deficient (Col6a1−/−) mice. Immunofluorescence-guided atomic force microscopy was used to map PCM Mechanical properties based on the presence of perlecan. Results Hypo-osmotic stress–induced TRPV4-mediated calcium Signaling was increased in Col6a1−/− mice relative to WT controls at 2 months. Col6a1−/− mice exhibited significantly increased osmotically induced cell swelling and decreased PCM moduli relative to WT controls at both ages. Conclusion In contrast to our original hypothesis, type VI collagen was not required for TRPV4-mediated Ca2+ Signaling; however, knockout of type VI collagen altered the Mechanical properties of the PCM, which in turn increased the extent of cell swelling and osmotically induced TRPV4 Signaling in an age-dependent manner. These findings emphasize the role of the PCM as a transducer of Mechanical and physicochemical Signals, and they suggest that alterations in PCM properties, as may occur with aging or osteoarthritis, can influence mechanotransduction via TRPV4 or other ion channels.
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Chondroprotective role of the osmotically sensitive ion channel transient receptor potential vanilloid 4: age- and sex-dependent progression of osteoarthritis in Trpv4-deficient mice.
Arthritis & Rheumatism, 2010Co-Authors: A.l. Clark, Bartholomew J. Votta, Wolfgang Liedtke, Sanjay Kumar, Farshid GuilakAbstract:Objectives Mechanical loading significantly influences the physiology and pathology of articular cartilage, although the mechanisms of Mechanical Signal transduction are not fully understood. Transient receptor potential vanilloid 4 (TRPV4) is a calcium (Ca++) permeable ion channel that is highly expressed by articular chondrocytes and can be gated by osmotic and Mechanical stimuli. The goal of this study was to determine the role of Trpv4 on the structure of the mouse knee joint and to determine whether Trpv4−/− mice exhibit altered Ca++ Signaling in response to osmotic challenge.
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the Mechanical environment of the chondrocyte a biphasic finite element model of cell matrix interactions in articular cartilage
Journal of Biomechanics, 2000Co-Authors: Farshid GuilakAbstract:Abstract Mechanical compression of the cartilage extracellular matrix has a significant effect on the metabolic activity of the chondrocytes. However, the relationship between the stress–strain and fluid-flow fields at the macroscopic “tissue” level and those at the microscopic “cellular” level are not fully understood. Based on the existing experimental data on the deformation behavior and bioMechanical properties of articular cartilage and chondrocytes, a multi-scale biphasic finite element model was developed of the chondrocyte as a spheroidal inclusion embedded within the extracellular matrix of a cartilage explant. The Mechanical environment at the cellular level was found to be time-varying and inhomogeneous, and the large difference (∼3 orders of magnitude) in the elastic properties of the chondrocyte and those of the extracellular matrix results in stress concentrations at the cell–matrix border and a nearly two-fold increase in strain and dilatation (volume change) at the cellular level, as compared to the macroscopic level. The presence of a narrow “pericellular matrix” with different properties than that of the chondrocyte or extracellular matrix significantly altered the principal stress and strain magnitudes within the chondrocyte, suggesting a functional bioMechanical role for the pericellular matrix. These findings suggest that even under simple compressive loading conditions, chondrocytes are subjected to a complex local Mechanical environment consisting of tension, compression, shear, and fluid pressure. Knowledge of the local stress and strain fields in the extracellular matrix is an important step in the interpretation of studies of Mechanical Signal transduction in cartilage explant culture models.
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the Mechanical environment of the chondrocyte a biphasic finite element model of cell matrix interactions in articular cartilage
Journal of Biomechanics, 2000Co-Authors: Farshid Guilak, Van C MowAbstract:Mechanical compression of the cartilage extracellular matrix has a significant effect on the metabolic activity of the chondrocytes. However, the relationship between the stress-strain and fluid-flow fields at the macroscopic "tissue" level and those at the microscopic "cellular" level are not fully understood. Based on the existing experimental data on the deformation behavior and bioMechanical properties of articular cartilage and chondrocytes, a multi-scale biphasic finite element model was developed of the chondrocyte as a spheroidal inclusion embedded within the extracellular matrix of a cartilage explant. The Mechanical environment at the cellular level was found to be time-varying and inhomogeneous, and the large difference ( approximately 3 orders of magnitude) in the elastic properties of the chondrocyte and those of the extracellular matrix results in stress concentrations at the cell-matrix border and a nearly two-fold increase in strain and dilatation (volume change) at the cellular level, as compared to the macroscopic level. The presence of a narrow "pericellular matrix" with different properties than that of the chondrocyte or extracellular matrix significantly altered the principal stress and strain magnitudes within the chondrocyte, suggesting a functional bioMechanical role for the pericellular matrix. These findings suggest that even under simple compressive loading conditions, chondrocytes are subjected to a complex local Mechanical environment consisting of tension, compression, shear, and fluid pressure. Knowledge of the local stress and strain fields in the extracellular matrix is an important step in the interpretation of studies of Mechanical Signal transduction in cartilage explant culture models.
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viscoelastic properties of the cell nucleus
Biochemical and Biophysical Research Communications, 2000Co-Authors: Farshid Guilak, John Tedrow, Rainer BurgkartAbstract:Mechanical factors play an important role in the regulation of cell physiology. One pathway by which Mechanical stress may influence gene expression is through a direct physical connection from the extracellular matrix across the plasma membrane and to the nucleus. However, little is known of the Mechanical properties or deformation behavior of the nucleus. The goal of this study was to quantify the viscoelastic properties of Mechanically and chemically isolated nuclei of articular chondrocytes using micropipet aspiration in conjunction theoretical viscoelastic model. Isolated nuclei behaved as viscoelastic solid materials similar to the cytoplasm, but were 3-4 times stiffer and nearly twice as viscous as the cytoplasm. Quantitative information of the biophysical properties and deformation behavior of the nucleus may provide further insight on the relationships between the stress-strain state of the nucleus and that of the extracellular matrix, as well as potential mechanisms of Mechanical Signal transduction.
Kay Hamacher - One of the best experts on this subject based on the ideXlab platform.
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Mechanical transduction of cytoplasmic to transmembrane domain movements in a hyperpolarization activated cyclic nucleotide gated cation channel
Journal of Biological Chemistry, 2018Co-Authors: Christine Gross, Andrea Saponaro, Bina Santoro, Anna Moroni, Gerhard Thiel, Kay HamacherAbstract:: Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels play a critical role in the control of pacemaking in the heart and repetitive firing in neurons. In HCN channels, the intracellular cyclic nucleotide-binding domain (CNBD) is connected to the transmembrane portion of the channel (TMPC) through a helical domain, the C-linker. Although this domain is critical for Mechanical Signal transduction, the conformational dynamics in the C-linker that transmit the nucleotide-binding Signal to the HCN channel pore are unknown. Here, we use linear response theory to analyze conformational changes in the C-linker of the human HCN1 protein, which couple cAMP binding in the CNBD with gating in the TMPC. By applying a force to the tip of the so-called "elbow" of the C-linker, the coarse-grained calculations recapitulate the same conformational changes triggered by cAMP binding in experimental studies. Furthermore, in our simulations, a displacement of the C-linker parallel to the membrane plane (i.e. horizontally) induced a rotational movement resulting in a distinct tilting of the transmembrane helices. This movement, in turn, increased the distance between the voltage-sensing S4 domain and the surrounding transmembrane domains and led to a widening of the intracellular channel gate. In conclusion, our computational approach, combined with experimental data, thus provides a more detailed understanding of how cAMP binding is Mechanically coupled over long distances to promote voltage-dependent opening of HCN channels.
Christine Gross - One of the best experts on this subject based on the ideXlab platform.
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Mechanical transduction of cytoplasmic to transmembrane domain movements in a hyperpolarization activated cyclic nucleotide gated cation channel
Journal of Biological Chemistry, 2018Co-Authors: Christine Gross, Andrea Saponaro, Bina Santoro, Anna Moroni, Gerhard Thiel, Kay HamacherAbstract:: Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels play a critical role in the control of pacemaking in the heart and repetitive firing in neurons. In HCN channels, the intracellular cyclic nucleotide-binding domain (CNBD) is connected to the transmembrane portion of the channel (TMPC) through a helical domain, the C-linker. Although this domain is critical for Mechanical Signal transduction, the conformational dynamics in the C-linker that transmit the nucleotide-binding Signal to the HCN channel pore are unknown. Here, we use linear response theory to analyze conformational changes in the C-linker of the human HCN1 protein, which couple cAMP binding in the CNBD with gating in the TMPC. By applying a force to the tip of the so-called "elbow" of the C-linker, the coarse-grained calculations recapitulate the same conformational changes triggered by cAMP binding in experimental studies. Furthermore, in our simulations, a displacement of the C-linker parallel to the membrane plane (i.e. horizontally) induced a rotational movement resulting in a distinct tilting of the transmembrane helices. This movement, in turn, increased the distance between the voltage-sensing S4 domain and the surrounding transmembrane domains and led to a widening of the intracellular channel gate. In conclusion, our computational approach, combined with experimental data, thus provides a more detailed understanding of how cAMP binding is Mechanically coupled over long distances to promote voltage-dependent opening of HCN channels.
Elisabeth R Barton - One of the best experts on this subject based on the ideXlab platform.
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restoration of γ sarcoglycan localization and Mechanical Signal transduction are independent in murine skeletal muscle
Journal of Biological Chemistry, 2010Co-Authors: Elisabeth R BartonAbstract:Limb girdle muscular dystrophy 2C is caused by mutations in the γ-sarcoglycan gene (gsg) that results in loss of this protein, and disruption of the sarcoglycan (SG) complex. Signal transduction after Mechanical perturbation is mediated, in part, through the SG complex and leads to phosphorylation of tyrosines on the intracellular portions of the sarcoglycans. This study tested if the Tyr6 in the intracellular region of γ-sarcoglycan protein (γ-SG) was necessary for proper localization of the protein in skeletal muscle membranes or for the normal pattern of ERK1/2 phosphorylation after eccentric contractions. Viral mediated gene transfer of wild type gsg (WTgsg) and mutant gsg lacking Tyr6 (Y6Agsg) was performed into the muscles of gsg−/− mice. Muscles were examined for production and stability of the γ-SG, as well as the level of ERK1/2 phosphorylation before and after eccentric contraction. Sarcolemmal localization of γ-SG was achieved regardless of which construct was expressed. However, only expression of WTgsg corrected the aberrant ERK1/2 phosphorylation associated with the absence of γ-SG, whereas Y6Agsg failed to have any effect. This study shows that localization of γ-SG does not require Tyr6, but localization alone is insufficient for restoration of normal Signal transduction patterns after Mechanical perturbation.
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impact of sarcoglycan complex on Mechanical Signal transduction in murine skeletal muscle
American Journal of Physiology-cell Physiology, 2006Co-Authors: Elisabeth R BartonAbstract:Loss of the dystrophin glycoprotein complex (DGC) or a subset of its components can lead to muscular dystrophy. However, the patterns of symptoms differ depending on which proteins are affected. Ab...
Andrea Saponaro - One of the best experts on this subject based on the ideXlab platform.
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Mechanical transduction of cytoplasmic to transmembrane domain movements in a hyperpolarization activated cyclic nucleotide gated cation channel
Journal of Biological Chemistry, 2018Co-Authors: Christine Gross, Andrea Saponaro, Bina Santoro, Anna Moroni, Gerhard Thiel, Kay HamacherAbstract:: Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels play a critical role in the control of pacemaking in the heart and repetitive firing in neurons. In HCN channels, the intracellular cyclic nucleotide-binding domain (CNBD) is connected to the transmembrane portion of the channel (TMPC) through a helical domain, the C-linker. Although this domain is critical for Mechanical Signal transduction, the conformational dynamics in the C-linker that transmit the nucleotide-binding Signal to the HCN channel pore are unknown. Here, we use linear response theory to analyze conformational changes in the C-linker of the human HCN1 protein, which couple cAMP binding in the CNBD with gating in the TMPC. By applying a force to the tip of the so-called "elbow" of the C-linker, the coarse-grained calculations recapitulate the same conformational changes triggered by cAMP binding in experimental studies. Furthermore, in our simulations, a displacement of the C-linker parallel to the membrane plane (i.e. horizontally) induced a rotational movement resulting in a distinct tilting of the transmembrane helices. This movement, in turn, increased the distance between the voltage-sensing S4 domain and the surrounding transmembrane domains and led to a widening of the intracellular channel gate. In conclusion, our computational approach, combined with experimental data, thus provides a more detailed understanding of how cAMP binding is Mechanically coupled over long distances to promote voltage-dependent opening of HCN channels.