Project Summary Contemporary evidence highlights a doubling of osteoarthritis (OA) prevalence in the post-industrial era; suggesting that OA might represent a ‘mismatch disease’. It has been suggested that the ‘mismatch’ underlying OA is our increasingly sedentary and inactive modern lifestyle. While mythos has led some to believe that physical activity endangers joint health, reality is far different; moderately- to highly-active individuals experience no increase in OA risk, but instead prolonged joint health. Conversely, increased sedentary inactivity appears associated with OA risk. However, the biomechanical, cellular, and molecular mechanisms underlying the differential effects of activity on cartilage health remain largely unresolved; partly due a lack of tools for studying these phenomena under well-controlled and physiologically-consistent sliding environments ex vivo. Recently, our team has leveraged a long-forgotten bench-top cartilage testing configuration, the convergent stationary contact area (cSCA), to fundamentally transform our understanding of how articular cartilage biomechanics (i.e. deformation & hydration) and tribology (i.e. lubrication and wear resistance) are enhanced by activity and compromised by inactivity. This unique tool represents the first (and only) explant testing platform to allow precisely controlled operation under truly physiologically conditions (high applied stresses, interstitial pressures, & sliding speeds; and moderate strains, & low friction/shears) for biologically relevant durations (hours to days). Moreover, the ability to easily model ‘daily’ joint activities via the cSCA has allowed us to use this platform to demonstrate how increasing activity frequency and decreasing continuous sedentary bout length tribomechanically benefits cartilage by preventing load-induced tissue strain and loss of hydration, thereby buffering against wear inducing friction. Combining our recent cSCA-derived understanding of cartilage tribomechanics with established studies linking losses of interstitial pressure and lubrication to chondrocyte dysfunction and tissue catabolism, we posit that activity-modulated recovery of tissue hydration is a critical and under-recognized regulator of cartilage tribomechanics, chondrocyte homeostasis, and joint health, and that modern, post-industrial increases in OA prevalence likely reflect simple mechanobiological consequences of chronic prolonged inactivity compromising the functional competency of cartilage. The goal of this proposal is to leverage the unique physiological relevance, experimental precision, and cellular interrogation capabilities of the cSCA platform to i) establish critical predictive relationships between activity volume, activity frequency, cartilage’s sliding biomechanics, and in situ chondrocyte homeostasis and ii) Identify how cartilage injury alters the relationships between activity, sliding biomechanics, and in situ chondrocyte homeostasis. The findings from this research will generate new knowledge regarding the basic mechanobiological function of articular cartilage and will help to inform rationally based and mechanistically grounded activity prescriptions for promoting and maintaining cartilage and joint longevity in healthy and injured joints.