The Influence of Sedentary vs. Active Lifestyles on Chondrocyte Homeostasis and Cartilage Health: A Novel Benchtop Explant Study

项目摘要 当代证据显示，在后工业时代，骨关节炎（OA）患病率翻了一番; 提示OA可能代表一种“错配性疾病”。有人认为，“不匹配”的基础 OA是我们越来越久坐不动的现代生活方式。虽然神话让一些人相信， 体力活动危害关节健康，现实情况远非如此;中度至高度活跃的个人经历 没有增加OA风险，而是延长了关节健康。相反，久坐不动的情况增加， 与OA风险有关。然而，生物力学，细胞和分子机制的基础上， 活动对软骨健康的不同影响在很大程度上仍未得到解决;部分原因是缺乏研究工具 这些现象在离体良好控制且生理一致的滑动环境下发生。最近， 我们的团队利用了一种被遗忘已久的台式软骨测试配置， 接触面积（cSCA），从根本上改变我们对关节软骨生物力学（即， 变形和水合作用）和摩擦学（即润滑和耐磨性）通过活性增强， 因为不活动而受损这种独特的工具代表了第一个（也是唯一一个）外植体测试平台， 在真正的生理条件下（高施加应力，间隙压力， 和滑动速度;和适度的应变，和低摩擦/剪切）的生物相关的持续时间（小时至天）。 此外，通过cSCA轻松建模“日常”联合活动的能力使我们能够使用该平台， 演示如何增加活动频率和减少连续久坐回合长度 摩擦力学通过防止负荷引起的组织应变和水合作用的损失而有益于软骨， 缓冲磨损引起的摩擦。结合我们最近cSCA对软骨的理解， 摩擦力学与已建立的研究联系起来的间隙压力和润滑软骨细胞的损失 功能障碍和组织catenary，我们认为，活动调节恢复组织水合作用是一个关键， 软骨摩擦力学、软骨细胞稳态和关节健康的未被充分认识的调节剂， 现代后工业时代OA患病率的增加可能反映了 慢性长期不活动损害软骨的功能能力。本提案的目的是 利用独特的生理相关性，实验精度，和细胞的审讯能力， cSCA平台，i）建立活动量、活动频率 软骨的滑动生物力学和原位软骨细胞稳态，以及ii）确定软骨损伤如何改变 活动、滑动生物力学和原位软骨细胞稳态之间的关系。的结果 这项研究将产生关于关节软骨基本机械生物学功能的新知识。 并将有助于提供合理的和机械的活动处方，以促进和 保持健康和受伤关节的软骨和关节寿命。

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.