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

久坐与活跃生活方式对软骨细胞稳态和软骨健康的影响：一项新型台式外植体研究

• 批准号: 10091025
• 负责人: Christopher Price
• 金额: $ 15.31万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10091025
• 关键词: Address; Adverse effects; Affect; Anabolism; Apoptosis; Area; Automobile Driving; Biological; Biomechanics; Buffers; Cartilage; Cartilage injury; Catabolism; Chondrocytes; Chronic; Competence; Degenerative polyarthritis; Delaware; Disease; Environment; Foundations; Frequencies; Friction; Functional disorder; Gene Expression; Geometry; Glass; Goals; Health; Homeostasis; Hour; Hydration status; In Situ; Individual; Industrialization; Inflammatory; Injury; Joints; Knowledge; Length; Life Style; Link; Liquid substance; Longevity; Lubrication; Mechanics; Mediating; Modeling; Modernization; Molecular; Musculoskeletal; Outcome; Pattern; Performance; Physical activity; Physiological; Play; Prevalence; Process; Protocols documentation; Recovery; Regression Analysis; Rehydrations; Research; Resistance; Risk; Role; Signal Transduction; Slide; Speed; Stress; Surface; System; Testing; Tissues; Work; active lifestyle; articular cartilage; base; epidemiology study; experience; hydrodynamic flow; interfacial; interstitial; joint injury; mechanical behavior; novel; operation; pressure; prevent; programs; response; sedentary; sedentary lifestyle; tool; translational study

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.

项目摘要 当代证据凸显了后工业时代的两次骨关节炎（OA）患病率。 表明OA可能代表“不匹配疾病”。有人建议底层的“不匹配” OA是我们日益久坐和不活跃的现代生活方式。虽然神话使一些人相信 体育活动危害了联合健康，现实却大不相同。中度至高度活跃的人经历 OA风险没有增加，而是延长了关节健康。相反，出现久坐不可能增加 与OA风险相关。但是，生物力学，细胞和分子机制 活动对软骨健康的差异影响在很大程度上尚未解决；部分原因是缺乏学习工具 这些现象在良好的控制和身体上一致的滑动环境中。最近， 我们的团队利用了长期遗忘的台式软骨测试配置，即收敛的固定 接触区域（CSCA），从根本上改变了我们对关节软骨生物力学的理解（即 变形与水合）和摩擦学（即润滑和耐磨性）通过活动和 因不活动而妥协。这个唯一的工具代表了第一个（也是唯一的）epplant测试平台 精确控制的操作在真正的身体状况下（高施加的应力，间质压力， 和滑动速度；和中等的菌株，低摩擦/剪切），用于生物学相关的持续时间（小时到几天）。 此外，通过CSCA轻松建模“每日”联合活动的能力使我们能够使用此平台 证明活动频率增加并降低连续久坐的回合长度 通过防止负荷诱导的组织应变和水合损失，摩擦力学上有益于软骨 防止磨损诱导的摩擦。结合我们最近对软骨的CSCA衍生的理解 摩托学与既定的研究，将间质压力和润滑与软骨细胞的损失联系起来 功能障碍和组织分解代谢，我们阳性组织水合的恢复是关键的，并且 软骨力学，软骨细胞体内平衡和联合健康的不足认可的调节剂 OA患病率的现代后工业化增加可能反映了简单的机械后果 慢性延长不活动损害了软骨的功能性。该提议的目的是 利用独特的生理相关性，实验精度和细胞询问能力 CSCA平台i）建立活动量，活动频率， 软骨的滑动生物力学以及原位软骨细胞体内平衡和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体内平衡之间的关系。来自 这项研究将产生有关关节软骨的基本机械功能的新知识 并将有助于为促进和机械基础的活动处方提供信息 在健康和受伤的关节中维持软骨和关节寿命。