Probing Osteoarthritis Pathogenesis by Noninvasive Imaging of Cartilage Strain

描述（由申请人提供）：本研究的总体目的是确定可单独使用新型位移编码MRI（deMRI）以及与常规成像和生物标志物测定联合使用检测的骨关节炎（OA）的最早期。OA是一种使人衰弱的疾病，困扰着美国近20%的人。为了开发一种成像生物标志物，在OA进展期间非侵入性地跟踪软骨中的结构变性，我们利用deMRI测量体内软骨外植体和完整关节内部的机械应变。随着deMRI的发展，我们现在准备评估deMRI在诊断软骨早期结构和机械变化方面的实用性和转化，这些变化可能使关节易于恶化，但尚未完全进展为OA。我们将使用三种已建立的OA模型，这些模型代表生物学、机械性创伤和体内联合治疗，导致可再现的退化模式。通过比较deMRI，定量MRI（qMRI）和生物学（例如细胞因子）测定，我们将跟踪变性的时间过程，并确定机械解释deMRI变化的关键分子。我们将进一步确定早期OA检测的最佳MRI序列组合，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。在目标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性细胞因子和选择性酶改变。为了解释菌株变化，还将监测分解代谢因子、基质含量和组织结构的相应表达。在目标2中，我们将测量体外机械损伤后3D软骨应变的时空变化。建立的压缩损伤模型将用于研究通过deMRI检测到的软骨结构退化和机械应变变化的进展，这将与已知在软骨软骨细胞中上调和下调的基因的表达相关。在目标3中，我们将在体内OA发病机制的动物模型中比较成像和生化生物标志物。我们将在时间上比较deMRI与qMRI、组织学和组织化学终点以及来自血清和滑液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领域提供（a）一种临床诊断工具，以评估动物和人体试验中针对早期OA的治疗药物，（B）功能性评估组织愈合的能力，以及新兴组织工程方法的修复，以及（c）一种平台技术，以更广泛地研究体内承重组织（例如半月板，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.