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: 10352306
• 负责人: Christopher Price
• 金额: $ 3.38万
• 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 2021-02-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10352306
• 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.

项目概要 当代证据表明，后工业时代骨关节炎（OA）患病率翻了一番； 表明 OA 可能代表一种“错配疾病”。有人认为，“错配”是潜在的。 OA 是我们越来越久坐和不活动的现代生活方式，而一些神话让一些人相信这一点。 体力活动会危害关节健康，但中度到高度活动的人的实际情况却大不相同； 骨关节炎风险并没有增加，而是关节健康状况延长，久坐不动的情况增加。 然而，其背后的生物力学、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； 最近，这些现象是在良好控制和生理一致的体外滑动环境下发生的。 我们的团队利用了一种长期被遗忘的台式软骨测试配置，即收敛固定式 接触面积（cSCA），从根本上改变我们对关节软骨生物力学的理解（即。 变形和水合作用）和摩擦学（即润滑和耐磨性）通过活动和 这种独特的工具代表了第一个（也是唯一一个）允许的外植体测试平台。 在真正的生理条件下精确控制操作（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）与生物学相关的持续时间（几小时到几天）。 此外，通过 cSCA 轻松模拟“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持续久坐时间 通过防止负载引起的组织应变和水合损失，在摩擦力学上有益于软骨，从而 结合我们最近对软骨的理解来缓冲磨损。 摩擦力学与已建立的研究将间质压力和润滑的损失与软骨细胞联系起来 功能障碍和组织分解代谢，我们认为活动调节的组织水合作用恢复是一个关键且重要的因素。 软骨摩擦力学、软骨细胞稳态和关节健康的调节剂尚未得到充分认识 现代、后工业时代 OA 患病率的增加可能反映了简单的机械生物学后果 长期不活动会损害软骨的功能 该提案的目标是 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) 在活动量、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。 这项研究将产生有关关节软骨基本机械生物学功能的新知识 并将有助于为促进和促进基于理性和机械性的活动处方提供信息 维持健康和受伤关节的软骨和关节寿命。