Direct measurement of TRPV4 and PIEZO1 activity reveals multiple mechanotransduction pathways in chondrocytes

Cartilage is a flexible tissue that cushions the joints in our body, allowing them to move smoothly. It is made of cells called chondrocytes that are surrounded by a scaffold of proteins known as the extracellular matrix. Chondrocytes regularly experience mechanical forces, which can arise from the movement of fluid within the joints or be transmitted to chondrocytes via the extracellular matrix. These cells sense mechanical forces by a process known as mechanotransduction, which allows chondrocytes to alter the composition of the extracellular matrix in order to maintain an appropriate amount of cartilage. If mechanotransduction pathways are disrupted, the cartilage may become damaged, which can result in osteoarthritis and other painful joint diseases. The membrane that surrounds a chondrocyte contains proteins known as ion channels that are responsible for sensing mechanical forces. The channels open in response to mechanical forces to allow ions to flow into the cell. This movement of ions generates electrical signals that result in changes to the production of extracellular matrix proteins. However, there is little direct evidence that mechanical forces can activate ion channels in chondrocytes and it not known how these cells respond to different types of forces. To address these questions, Servin-Vences et al. exposed chondrocytes from mice to mechanical forces either at the point of contact between the cell and its surrounding matrix, or to stretch the cell membrane. The experiments show that two ion channels called PIEZO1 and TRPV4 both generate electrical currents in response to forces transmitted between cells and the extracellular matrix. However, only PIEZO1 generates a current when the cell membrane is stretched. Thus, chondrocytes are able to distinguish between different types of mechanical forces. More work is needed to understand how mechanical forces are able to activate these ion channels. Understanding how these processes work at the molecular level will hopefully lead to new therapies that boost cartilage production to treat joint diseases.