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

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. From these studies, it is clear that there exists a complex interplay between mechanical, inflammatory, and biochemical factors that can either support or inhibit cartilage matrix homeostasis under normal or pathologic conditions. Understanding these interactions is an important step toward developing tissue engineering approaches and therapeutic interventions for cartilage pathologies.