Cartilage-Bone-Synovium MPS: Musculoskeletal Disease Biology in Space

软骨-骨-滑膜 MPS：太空中的肌肉骨骼疾病生物学

• 批准号: 9890032
• 负责人: ALAN J. GRODZINSKY
• 金额: $ 73.87万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9890032
• 关键词: Address; Analgesics; Antibodies; Astronauts; Behavior; Biological Markers; Biological Models; Biological Response Modifier Therapy; Biology; Cartilage; Cells; Clinical Trials; Coculture Techniques; Computing Methodologies; Data; Degenerative polyarthritis; Dexamethasone; Disease; Disease Progression; Glucocorticoids; Histologic; Human; Hyaluronic Acid; In Vitro; Incubators; Individual; Inflammation; Inflammatory; Injury; Interleukin-6; International; Joint Capsule; Joints; Knee; Lubricants; Mechanics; Microgravity; Mission; Modeling; Motion; Musculoskeletal Diseases; Musculoskeletal System; Outcome; Outcome Measure; Periodicity; Pharmaceutical Preparations; Pharmacology; Phase; Planet Earth; Process; Protein Analysis; Proteins; Protocols documentation; Readiness; Rehabilitation therapy; Replacement Arthroplasty; Research; Research Design; Space Flight; Synovial Fluid; Synovial Membrane; Synovial joint; System; TNF gene; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Tissues; Translations; Trauma; Up-Regulation; arthropathies; base; biomarker discovery; bone; bone loss; cartilage degradation; cytokine; drug efficacy; efficacy testing; experimental study; extracellular; in vivo; instrument; joint function; joint injury; mechanical load; metabolomics; microphysiology system; middle age; osteochondral tissue; pain relief; patient stratification; prevent; programs; response; response biomarker; small molecule; space station; subchondral bone; treatment response; treatment strategy

Project Summary/Abstract Our mission in this program is to bring highly quantitative and high-content experimental and computational approaches to study the effects of space flight on the musculoskeletal system, focusing on cartilage, bone and synovium. The musculoskeletal disease focus is post-traumatic osteoarthritis, an all too common condition initiated in otherwise healthy (young to middle-aged) individuals who suffer a joint injury. The interactions between cartilage, bone and synovium in human joints are critically important for joint function and human motion on earth and in long-term space flight. Upon traumatic joint injury, there is an immediate upregulation of inflammatory cytokines in the synovial fluid that are secreted primarily by cells in the synovial membrane. When combined with mechanical trauma to cartilage accompanying joint injury, degradation of cartilage as well as subchondral bone often progresses to post-traumatic osteoarthritis. To study these interactions and how they may be ameliorated both on earth and in space, we propose to co-culture primary human explants of intact (native) cartilage, bone and synovial joint capsule tissue (obtained from a long-standing collaborating human donor bank). We will then test the effects of selected pharmacological agents (e.g., the anti-catabolic glucocorticoid, dexamethasone, and an anti-bone resorptive anti-sclerostin antibody, to prevent bone loss) to ameliorate tissue degradative processes. To perform these studies, our Aims are to validate an MPS model using osteochondral plugs co-cultured with joint capsule synovium, to challenge this model with inflammatory cytokines and an initial impact injury (associated with the early phases of post-traumatic OA), treat these challenged co-cultures with selected pharmacological agents on earth and in the international space station, and to address issues of patient stratification for treatment strategies, human donor variability, and response to therapeutics via biomarker discovery. Endpoint analyses include intracellular and extracellular biomarkers assessed using quantitative metabolomics and multiplexed protein release analyses. In addition, we will test the possibility that an optimized mechanical loading protocol on earth, post-flight, could have specific pro- anabolic and anti-catabolic effects on osteochondral tissues and a suppression of inflammatory cytokines from the synovium.

项目摘要/摘要 我们在这个项目中的使命是将高数量和高内容的实验和计算 研究太空飞行对肌肉骨骼系统影响的方法，重点是软骨、骨骼和 滑膜。肌肉骨骼疾病的焦点是创伤后骨关节炎，这是一种非常常见的疾病。 在其他健康的(年轻到中年)遭受关节损伤的个人中开始。互动 关节中软骨、骨和滑膜之间的相互作用对关节功能和人体健康至关重要 在地球上和长期太空飞行中的运动。在创伤性关节损伤时，会立即上调 滑液中的炎性细胞因子，主要由滑膜细胞分泌。 当合并关节损伤时，软骨机械性损伤也会导致软骨退化。 由于软骨下骨通常进展为创伤后骨关节炎。研究这些相互作用以及如何 无论是在地球上还是在太空中，它们都可能得到改善，我们建议将原代人类外植体与 完整的(天然)软骨、骨和滑膜关节囊组织(从长期合作中获得 人类捐赠库)。然后，我们将测试选定的药理制剂(例如，抗分解代谢药)的效果 糖皮质激素、地塞米松和抗骨吸收抗硬化素抗体，以防止骨丢失) 改善组织降解过程。为了进行这些研究，我们的目标是验证MPS模型 用骨软骨栓与关节囊滑膜共培养，以炎性反应挑战该模型 细胞因子和最初的撞击性损伤(与创伤后骨性关节炎的早期阶段相关)，治疗这些 挑战与地球和国际空间站中选定的药理药剂的共培养， 并解决治疗策略的患者分层、人类供体的变异性和对 通过发现生物标记物进行治疗。终点分析包括细胞内和细胞外生物标志物 使用定量代谢组学和多重蛋白质释放分析进行评估。此外，我们还将测试 在飞行后，地球上优化的机械加载方案可能具有特定的优势。 骨软骨组织的合成代谢和抗分解代谢作用及对炎性细胞因子的抑制作用 滑膜。

项目成果

Predicting transport of intra-articularly injected growth factor fusion proteins into human knee joint cartilage.

• DOI: 10.1016/j.actbio.2022.09.032
• 发表时间: 2022-09
• 期刊: Acta biomaterialia
• 影响因子: 9.7
• 作者: Y. Krishnan;Y. Yang;Sieun K. Barnes;H. Hung;B. Olsen;P. Hammond;A. Grodzinsky

Effects of dexamethasone and dynamic loading on cartilage of human osteochondral explants challenged with inflammatory cytokines.

• DOI: 10.1016/j.jbiomech.2023.111480
• 发表时间: 2023-02
• 期刊: Journal of biomechanics
• 影响因子: 2.4
• 作者: Hannah J. Szapary;Lisa Flaman;E. Frank;S. Chubinskaya;G. Dwivedi;A. Grodzinsky

DEXAMETHASONE: CHONDROPROTECTIVE CORTICOSTEROID OR CATABOLIC KILLER?

• DOI: 10.22203/ecm.v038a17
• 发表时间: 2019-07-01
• 期刊: EUROPEAN CELLS & MATERIALS
• 影响因子: 3.1
• 作者: Black, R.;Grodzinsky, A. J.
• 通讯作者: Grodzinsky, A. J.