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

项目总结/摘要 我们在这个项目中的使命是将高定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重点是创伤后骨关节炎，一个太常见的条件 在遭受关节损伤的其他健康（年轻至中年）个体中开始。的相互作用 人关节中软骨、骨和滑膜之间的相互作用对于关节功能和人 在地球上和长期太空飞行中的运动。在创伤性关节损伤后， 在滑膜液中的炎性细胞因子主要由滑膜中的细胞分泌。 当结合机械创伤软骨伴随关节损伤，软骨退化以及 因为软骨下骨经常发展为创伤后骨关节炎。研究这些相互作用以及如何 它们可能在地球上和太空中都得到改善，我们建议共培养原代人类外植体， 完整的（天然）软骨、骨和滑膜关节囊组织（从长期合作的 人类供体库）。然后，我们将测试选定的药理学试剂的作用（例如，抗分解代谢 糖皮质激素、地塞米松和抗骨吸收抗硬化蛋白抗体，以防止骨丢失）， 改善组织降解过程。为了进行这些研究，我们的目的是验证MPS模型 使用与关节囊滑膜共培养的骨软骨栓塞，用炎性 细胞因子和初始冲击损伤（与创伤后OA的早期阶段相关）， 在地球上和国际空间站上与选定的药物共同培养， 并解决治疗策略的患者分层、人类供体变异性和对 通过生物标志物发现的治疗方法。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，我们将测试 一个优化的机械加载协议在地球上的可能性，飞行后，可能有特定的亲， 对骨软骨组织的合成代谢和抗分解代谢作用以及对骨软骨炎性细胞因子的抑制， 滑膜

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.