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

Abstract

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. The goal of this study was to examine the hypothesis that TRPV4 transduces dynamic compressive loading in articular chondrocytes. We first confirmed the presence of physically induced, TRPV4-dependent intracellular Ca 2+ signaling in agarose-embedded chondrocytes, and then used this model system to study the role of TRPV4 in regulating the response of chondrocytes to dynamic compression. Inhibition of TRPV4 during dynamic loading prevented acute, mechanically mediated regulation of proanabolic and anticatabolic genes, and furthermore, blocked the loadinginduced enhancement of matrix accumulation and mechanical properties. Furthermore, chemical activation of TRPV4 by the agonist GSK1016790A in the absence of mechanical loading similarly enhanced anabolic and suppressed catabolic gene expression, and potently increased matrix biosynthesis and construct mechanical properties. These findings support the hypothesis that TRPV4-mediated Ca 2+ signaling plays a central role in the transduction of mechanical signals to support cartilage extracellular matrix maintenance and joint health. Moreover, these insights raise the possibility of therapeutically targeting TRPV4-mediated mechanotransduction for the treatment of diseases such as osteoarthritis, as well as to enhance matrix formation and functional properties of tissue-engineered cartilage as an alternative to bioreactor-based mechanical stimulation. mechanobiology | ion channel | calcium signaling | TGF-beta | tissue engineering

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

“…Our discovery provides, to our knowledge, the first direct evidence that mechanically sensitive ion channels in articular chondrocytes are necessary for these cells' response to high-strain mechanical cues. These findings complement recent results from our group reporting that the anabolic response of chondrocytes to low-level, physiologic mechanical loading, is regulated by a TRPV4-based mechanism (20). In addition, we have previously reported that loss of TRPV4 leads to age-dependent osteoarthritis in mice (19).…”

“…Although many different mechanisms have been shown to be involved in chondrocyte mechanotransduction (13,(15)(16)(17), recent studies show that the cation channel, TRPV4, is responsible for mediating the anabolic response of chondrocytes to osmotic or mechanical stress (18)(19)(20). In this regard, identification of the mechanosensitive pathways involved in cartilage homeostasis as well as injury will help to provide novel targets for rational treatment of cartilage injury and posttraumatic osteoarthritis (21).…”

Mechanical confinement regulates cartilage matrix formation by chondrocytes

“…While previous studies have found the importance of volume regulation by chondrocytes in cartilage physiology 42–44 , our work demonstrates that chondrocytes utilize changes in volume to sense the viscoelastic properties of their microenvironment. In adherent cells, it is known that cells sense viscoelasticity through exerting traction forces at integrin-ECM ligand adhesions, gauging resistance to traction forces, and clustering ligands 18,45–48 .…”

Systems approaches in osteoarthritis: Identifying routes to novel diagnostic and therapeutic strategies

“…Biomechanical signals are also multiscale responding to age and disease, Figure 3, with effects at a tissue level (differential loading across joint, load sharing across particular tissues), within a tissue (differential compression on zonal regions of cartilage) and cell‐associated (mechanotransduction through the pericellular matrix of the chondron) 61. Critically, there is not a single mechanical signal that transduces into an electrical or chemical signal intracellularly and different forces require a level of integration (compression, osmolarity, fluid shear, hydrostatic pressures); the contribution of each still needs to be defined 73. Given that mechanical signals have to be transduced through the extra‐ and peri‐cellular matrix to allow chondrocytes to respond to their physical environment mechanotransduction mechanisms are potential therapeutic targets.…”

“…Using a mechanistic approach a Ca 2+ responsive osmomechano‐TRP channel TRPV4 was found to be critical to transduction of mechanical and osmotic signals76 with enhanced anabolic gene expression and increased matrix production demonstrated using a chemical agonist 73. Further work, using a cartilage‐specific, inducible knock‐out of Trpv4 revealed a reduction in age‐associated OA at 12 months, but not in a DMM model 77.…”