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

项目摘要 当代证据表明，在后工业时代，骨关节炎(OA)的患病率翻了一番； 这表明骨性关节炎可能代表了一种“错配疾病”。有人认为，这种“不匹配”的根本原因是 办公自动化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 体育活动危及关节健康，现实大相径庭；中等至高度活跃的个人经历 骨性关节炎的风险没有增加，反而延长了关节健康。相反，久坐不动的现象会增加。 与骨性关节炎风险相关。然而，潜在的生物力学、细胞和分子机制 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 这些现象发生在受控良好且生理上一致的体外滑动环境中。最近， 我们的团队利用了一种早已被遗忘的台式软骨测试配置，即收敛固定器 接触面积(CSCA)，从根本上改变我们对关节软骨生物力学(即关节软骨)的理解。 变形和水化)和摩擦学(即润滑性和耐磨性)通过活动和 因无所事事而受到损害。这一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进行精确控制的操作(高应力、间质压力、 &滑动速度；以及中等应变和低摩擦/剪切)，用于生物相关的持续时间(几小时到几天)。 此外，通过CSCA轻松地模拟日常联合活动的能力使我们能够使用该平台来 演示如何增加活动频率和减少连续的久坐比赛时间 摩擦力学通过防止负荷引起的组织应变和水合丧失而有益于软骨，从而 缓冲磨损引起的摩擦。结合我们最新的CSCA对软骨的理解 摩擦力学与软骨细胞间质压力和润滑性损失有关的已有研究 功能障碍和组织分解代谢，我们假设活动调节的组织水合恢复是一个关键和 软骨摩擦力学、软骨细胞动态平衡和关节健康的调节机制未得到充分认识 现代、后工业时代骨性关节炎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。这项提议的目标是 利用独特的生理相关性、实验精确度和细胞询问功能 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动态平衡和ii)确定软骨损伤是如何改变的 活动度、滑动生物力学与软骨细胞原位稳态的关系。调查结果来自 这项研究将对关节软骨的基本机械生物学功能产生新的认识 并将有助于提供基于理性和机械基础的活动处方，以促进和 在健康和受伤的关节中保持软骨和关节寿命。

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.