Transient receptor potential vanilloid 4 as a regulator of induced pluripotent stem cell chondrogenesis.

Transient receptor potential vanilloid 4 (TRPV4) is a polymodal calcium-permeable cation channel that is highly expressed in cartilage and is sensitive to a variety of extracellular stimuli. The expression of this channel has been associated with the process of chondrogenesis in adult stem cells as well as several cell lines. Here, we used a chondrogenic reporter (Col2a1-GFP) in murine induced pluripotent stem cells (iPSCs) to examine the hypothesis that TRPV4 serves as both a marker and a regulator of chondrogenesis.

Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis.

Osteoarthritis (OA) is a painful and debilitating condition of synovial joints without any disease-modifying therapies [A. M. Valdes, T.

Obesity alters the collagen organization and mechanical properties of murine cartilage.

Osteoarthritis is a debilitating disease characterized by cartilage degradation and altered cartilage mechanical properties. Furthermore, it is well established that obesity is a primary risk factor for osteoarthritis. The purpose of this study was to investigate the influence of obesity on the mechanical properties of murine knee cartilage.

Type VI Collagen Regulates Pericellular Matrix Properties, Chondrocyte Swelling, and Mechanotransduction in Mouse Articular Cartilage.

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.

TRPV4 as a therapeutic target for joint diseases.

Biomechanical factors play a critical role in regulating the physiology as well as the pathology of multiple joint tissues and have been implicated in the pathogenesis of osteoarthritis. Therefore, the mechanisms by which cells sense and respond to mechanical signals may provide novel targets for the development of disease-modifying osteoarthritis drugs (DMOADs). Transient receptor potential vanilloid 4 (TRPV4) is a Ca(2+)-permeable cation channel that serves as a sensor of mechanical or osmotic signals in several musculoskeletal tissues, including cartilage, bone, and synovium.

Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage.

Diarthrodial joints are essential for load bearing and locomotion. Physiologically, articular cartilage sustains millions of cycles of mechanical loading. Chondrocytes, the cells in cartilage, regulate their metabolic activities in response to mechanical loading.

The mechanobiology of articular cartilage: bearing the burden of osteoarthritis.

Articular cartilage injuries and degenerative joint diseases are responsible for progressive pain and disability in millions of people worldwide, yet there is currently no treatment available to restore full joint functionality. As the tissue functions under mechanical load, an understanding of the physiologic or pathologic effects of biomechanical factors on cartilage physiology is of particular interest. Here, we highlight studies that have measured cartilage deformation at scales ranging from the macroscale to the microscale, as well as the responses of the resident cartilage cells, chondrocytes, to mechanical loading using in vitro and in vivo approaches.

Follistatin in chondrocytes: the link between TRPV4 channelopathies and skeletal malformations.

Point mutations in the calcium-permeable TRPV4 ion channel have been identified as the cause of autosomal-dominant human motor neuropathies, arthropathies, and skeletal malformations of varying severity. The objective of this study was to determine the mechanism by which TRPV4 channelopathy mutations cause skeletal dysplasia. The human TRPV4(V620I) channelopathy mutation was transfected into primary porcine chondrocytes and caused significant (2.

TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading.

Mechanical loading of joints plays a critical role in maintaining the health and function of articular cartilage. The mechanism(s) of chondrocyte mechanotransduction are not fully understood, but could provide important insights into new physical or pharmacologic therapies for joint diseases. Transient receptor potential vanilloid 4 (TRPV4), a Ca(2+)-permeable osmomechano-TRP channel, is highly expressed in articular chondrocytes, and loss of TRPV4 function is associated with joint arthropathy and osteoarthritis.

Unraveling the mechanism by which TRPV4 mutations cause skeletal dysplasias.

Transient Receptor Potential Vanilloid 4 (TRPV4) is a mechano- and osmosensitive cation channel that is highly expressed in chondrocytes, the cells in cartilage. A large number of mutations in TRPV4 have been linked to skeletal dysplasias, and the goal of this addendum is to shed light on the mechanisms by which mutations in TRPV4 can cause skeletal dysplasias by focusing on 3 recent publications. These papers suggest that skeletal dysplasia-causing TRPV4 mutations reprogram chondrocytes to increase follistatin production, which inhibits BMP signaling, thus slowing the process of endochondral ossification and leading to skeletal dysplasia.

High body mass index is associated with increased diurnal strains in the articular cartilage of the knee.

Objective: Obesity is an important risk factor for osteoarthritis (OA) and is associated with changes in both the biomechanical and inflammatory environments within the joint. However, the relationship between obesity and cartilage deformation is not fully understood. The goal of this study was to determine the effects of body mass index (BMI) on the magnitude of diurnal cartilage strain in the knee.

Synovial fluid concentrations and relative potency of interleukin-1 alpha and beta in cartilage and meniscus degradation.

Cartilage degeneration with osteoarthritis (OA) is believed to involve the activities of interleukin-1 (IL-1), which exists as alpha and beta isoforms. The goal of this study was to measure the concentrations of both isoforms of IL-1 in the synovial fluid of normal and spontaneously osteoarthritic porcine knees, and to test the hypothesis that physiologic concentrations of IL-1α and IL-1β exhibit different potencies in activating calcium signaling, the production of matrix metalloproteinases and nitric oxide, and the loss of proteoglycans and tissue mechanical properties in cartilage and meniscus. Median concentrations of IL-1α were 0.

Diurnal variations in articular cartilage thickness and strain in the human knee.

Due to the biphasic viscoelastic nature of cartilage, joint loading may result in deformations that require times on the order of hours to fully recover. Thus, cartilaginous tissues may exhibit cumulative strain over the course of each day. The goal of this study was to assess the magnitude and spatial distribution of strain in the articular cartilage of the knee with daily activity.

Effects of myocardial infarction on the distribution and transport of nutrients and oxygen in porcine myocardium.

One of the primary limitations of cell therapy for myocardial infarction is the low survival of transplanted cells, with a loss of up to 80% of cells within 3 days of delivery. The aims of this study were to investigate the distribution of nutrients and oxygen in infarcted myocardium and to quantify how macromolecular transport properties might affect cell survival. Transmural myocardial infarction was created by controlled cryoablation in pigs.

Altered trabecular bone structure and delayed cartilage degeneration in the knees of collagen VI null mice.

Mutation or loss of collagen VI has been linked to a variety of musculoskeletal abnormalities, particularly muscular dystrophies, tissue ossification and/or fibrosis, and hip osteoarthritis. However, the role of collagen VI in bone and cartilage structure and function in the knee is unknown. In this study, we examined the role of collagen VI in the morphology and physical properties of bone and cartilage in the knee joint of Col6a1(-/-) mice by micro-computed tomography (microCT), histology, atomic force microscopy (AFM), and scanning microphotolysis (SCAMP).

Osmotic stress alters chromatin condensation and nucleocytoplasmic transport.

Osmotic stress is a potent regulator of biological function in many cell types, but its mechanism of action is only partially understood. In this study, we examined whether changes in extracellular osmolality can alter chromatin condensation and the rate of nucleocytoplasmic transport, as potential mechanisms by which osmotic stress can act. Transport of 10 kDa dextran was measured both within and between the nucleus and the cytoplasm using two different photobleaching methods.

Transient receptor potential vanilloid 4: The sixth sense of the musculoskeletal system?

The critical discovery in the past two decades of the transient receptor potential (TRP) superfamily of ion channels has revealed the potential mechanisms by which cells sense diverse stimuli beyond the prototypical "five senses," identifying ion channels that are gated by heat, cold, mechanical loading, osmolarity, and other physical and chemical stimuli. TRP vanilloid 4 (TRPV4) is a Ca(2+)-permeable nonselective cation channel that appears to play a mechanosensory or osmosensory role in several musculoskeletal tissues. In articular cartilage, TRPV4 exhibits osmotic sensitivity, controlling cellular volume recovery, and other physiologic responses to osmotic stress.

Functional characterization of TRPV4 as an osmotically sensitive ion channel in porcine articular chondrocytes.

Objective: Transient receptor potential vanilloid 4 (TRPV4) is a Ca(2+)-permeable channel that can be gated by tonicity (osmolarity) and mechanical stimuli. Chondrocytes, the cells in cartilage, respond to their osmotic and mechanical environments; however, the molecular basis of this signal transduction is not fully understood. This study was undertaken to demonstrate the presence and functionality of TRPV4 in chondrocytes.

Microscale diffusion properties of the cartilage pericellular matrix measured using 3D scanning microphotolysis.

Chondrocytes, the cells in articular cartilage, are enclosed within a pericellular matrix (PCM) whose composition and structure differ from those of the extracellular matrix (ECM). Since the PCM surrounds each cell, molecules that interact with the chondrocyte must pass through the pericellular environment. A quantitative understanding of the diffusional properties of the PCM may help in elucidating the regulatory role of the PCM in controlling transport to and from the chondrocyte.

Site-specific effects of compression on macromolecular diffusion in articular cartilage.

Articular cartilage is the connective tissue that lines joints and provides a smooth surface for joint motion. Because cartilage is avascular, molecular transport occurs primarily via diffusion or convection, and cartilage matrix structure and composition may affect diffusive transport. Because of the inhomogeneous compressive properties of articular cartilage, we hypothesized that compression would decrease macromolecular diffusivity and increase diffusional anisotropy in a site-specific manner that depends on local tissue strain.

Zonal changes in the three-dimensional morphology of the chondron under compression: the relationship among cellular, pericellular, and extracellular deformation in articular cartilage.

The pericellular matrix (PCM) is a narrow region of tissue that completely surrounds chondrocytes in articular cartilage. Previous theoretical models of the "chondron" (the PCM with enclosed cells) suggest that the structure and properties of the PCM may significantly influence the mechanical environment of the chondrocyte. The objective of this study was to quantify changes in the three-dimensional (3D) morphology of the chondron in situ at different magnitudes of compression applied to the cartilage extracellular matrix.

Diffusional anisotropy in collagenous tissues: fluorescence imaging of continuous point photobleaching.

Molecular transport in avascular collagenous tissues such as articular cartilage occurs primarily via diffusion. The presence of ordered structures in the extracellular matrix may influence the local transport of macromolecules, leading to anisotropic diffusion depending on the relative size of the molecule and that of extracellular matrix structures. Here we present what we believe is a novel photobleaching technique for measuring the anisotropic diffusivity of macromolecules in collagenous tissues.

Composition and transport properties of human ankle and knee cartilage.

The incidence of osteoarthritis is significantly higher in the knee as compared to the ankle, suggesting that differences in the properties of cartilage from these joints may contribute to the development of osteoarthritis. As an avascular tissue, articular cartilage depends primarily upon diffusion for molecular transport. The goal of this study was to determine if differences in the structure and composition between ankle and knee cartilage were also reflected as differences in solute transport properties.

Adipose-derived adult stem cells for cartilage tissue engineering.

Tissue engineering is a promising therapeutic approach that uses combinations of implanted cells, biomaterial scaffolds, and biologically active molecules to repair or regenerate damaged or diseased tissues. Many diverse and increasingly complex approaches are being developed to repair articular cartilage, with the underlying premise that cells introduced exogenously play a necessary role in the success of engineered tissue replacements. A major consideration that remains in this field is the identification and characterization of appropriate sources of cells for tissue-engineered repair of cartilage.