Probing Osteoarthritis Pathogenesis by Noninvasive Imaging of Cartilage Strain

描述（由申请人提供）：本研究的总体目标是确定骨关节炎（OA）的最早阶段，该阶段可以单独使用新型位移编码MRI （deMRI）并结合传统成像和生物标志物检测来检测。OA是一种使人衰弱的疾病，在美国有近20%的人患有这种疾病。为了开发一种成像生物标志物，无创地跟踪OA进展过程中软骨的结构退行性变，我们利用deMRI测量软骨外植体和完整关节内部的机械应变。随着骨磁共振成像的发展，我们现在准备评估骨磁共振成像在诊断早期软骨结构和力学变化方面的应用和转化，这些变化可能使关节恶化，但尚未完全发展为骨关节炎。我们将使用三种已建立的OA模型，分别代表生物、机械创伤和体内联合治疗导致可重复的变性模式。通过比较deMRI，定量MRI （qMRI）和生物学（如细胞因子）测定，我们将跟踪变性的时间过程，并确定机制上解释deMRI变化的关键分子。我们将进一步确定早期OA检测MRI序列的最佳组合，并将在未来的研究中进行OA治疗药物的临床试验。我们将追求三个相关的具体目标。在目的1中，我们将在体外监测三维软骨应变的时空模式如何被炎症细胞因子和选择性酶改变。为了解释应变变化，还将监测相应的分解代谢因子、基质含量和组织结构的表达。在Aim 2中，我们将测量体外机械损伤后三维软骨应变的时空变化。我们将利用已建立的压缩损伤模型来研究软骨结构恶化的进展和deMRI检测到的机械应变变化，这将与软骨分解代谢中已知的上调和下调基因的表达有关。在Aim 3中，我们将比较OA体内发病动物模型中的影像学和生化生物标志物。我们将暂时比较deMRI和qMRI，组织学和组织化学终点，血清和滑液中的炎症和基质降解生物标志物。如果成功，这项工作将为骨科和肌肉骨骼社区提供(a)临床诊断工具来评估治疗药物在动物和人体试验中的早期OA， (b)功能评估组织愈合的能力，以及使用新兴的组织工程方法进行修复的能力，以及(c)平台技术来更广泛地研究体内承重组织（如半月板，韧带）的机械功能。

DESCRIPTION (provided by applicant): The overall objective of this study is to determine the earliest stage of osteoarthritis (OA) that can be detected using novel displacement-encoded MRI (deMRI) alone and in combination with conventional imaging and biomarker assays. OA is a debilitating disease that afflicts nearly 20% of people in the US. In an effort to develop an imaging biomarker that noninvasively tracks structural degeneration in cartilage during OA progression, we utilize deMRI for the measurement of mechanical strain in the interior of cartilage explants and intact joints in vivo. With the development of deMRI, we are now ready to assess the utility and translation of deMRI for diagnosing the early structural and mechanical changes to cartilage that may predispose the joint to deterioration but have not yet fully progressed to OA. We will use three established OA models that represent biological, mechanical trauma, and in vivo combined treatments leading to reproducible degeneration patterns. By comparing deMRI, quantitative MRI (qMRI), and biological (e.g. cytokine) assays, we will track the time course of degeneration and identify key molecules that mechanistically explain deMRI changes. We will further identify the best combination of MRI sequences for early OA detection, and will be positioned to perform clinical trials of therapeutic agents for OA treatment in future studies. We will pursue three related specific aims. In Aim 1, we will monitor in vitro how spatiotemporal patterns of 3D cartilage strain are altered by inflammatory cytokines and selective enzymes. To explain strain changes, the corresponding expression of catabolic factors, matrix content, and tissue structure, will also be monitored. In Aim 2, we will measure spatiotemporal changes in 3D cartilage strains following mechanical injury in vitro. An established compressive injury model will be used to study the progression of cartilage structural deterioration and mechanical strain changes detected by deMRI, which will be related to expression of genes known to be up- and down-regulated in cartilage catabolism. In Aim 3, we will compare imaging and biochemical biomarkers in an animal model of OA pathogenesis in vivo. We will temporally compare deMRI to qMRI, histology and histochemical endpoints, and inflammation and matrix degradation biomarkers from serum and synovial fluid. If successful, this work will provide orthopaedic and musculoskeletal communities with (a) a clinical diagnostic tool to evaluate therapeutic agents to target early OA in animal and human trials, (b) the ability to functionally evaluate tissue healing, and repair with emerging tissue engineering methods, and (c) a platform technology to more broadly study mechanical function of load-bearing tissues (e.g. meniscus, ligament) in vivo.