Probing Osteoarthritis Pathogenesis by Noninvasive Imaging of Cartilage Strain

描述(申请人提供)：这项研究的总体目标是确定可以单独使用新型位移编码磁共振成像(Demri)并结合传统成像和生物标记物分析检测到的骨关节炎(OA)的最早阶段。骨性关节炎是一种令人衰弱的疾病，在美国有近20%的人受到这种疾病的困扰。为了开发一种非侵入性跟踪OA进展过程中软骨结构退化的成像生物标记物，我们利用Demri在活体内测量软骨移植块和完整关节的机械应变。随着Demri的发展，我们现在已经准备好评估Demri在诊断软骨早期结构和力学变化方面的实用性和转换性，这些变化可能导致关节恶化，但尚未完全进展为OA。我们将使用三个已建立的OA模型，分别代表生物、机械创伤和体内联合治疗，从而导致可复制的退变模式。通过比较Demri、定量磁共振成像(QMRI)和生物学(如细胞因子)分析，我们将跟踪变性的时间过程，并确定从机制上解释Demri变化的关键分子。我们将进一步确定早期检测OA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，我们将在体外监测炎症细胞因子和选择性酶是如何改变3D软骨应变的时空模式的。为了解释菌株的变化，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。在目标2中，我们将在体外测量机械损伤后三维软骨应变的时空变化。已建立的压缩损伤模型将用于研究Demri检测到的软骨结构恶化和机械应变变化的进展，这将与软骨分解代谢中已知上调和下调的基因表达有关。在目标3中，我们将在体内比较OA发病的动物模型中的成像和生化生物标志物。我们将从时间上将Demri与qMRI、组织学和组织化学终点以及血清和滑液中的炎症和基质降解生物标记物进行比较。如果成功，这项工作将为骨科和肌肉骨骼界提供：(A)在动物和人类试验中评估针对早期骨关节炎的治疗药物的临床诊断工具，(B)从功能上评估组织愈合和利用新兴的组织工程方法进行修复的能力，以及(C)更广泛地研究体内承重组织(如半月板、韧带)的机械功能的平台技术。

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.