Probing Osteoarthritis Pathogenesis by Noninvasive Imaging of Cartilage Strain

通过软骨应变的无创成像探讨骨关节炎的发病机制

• 批准号: 9221761
• 负责人: Corey P Neu
• 金额: $ 20.28万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-05 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9221761
• 关键词: Probing; Osteoarthritis; Pathogenesis; Noninvasive; Imaging

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.

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) 以及与传统成像和生物标志物测定相结合来检测。骨关节炎是一种使人衰弱的疾病，困扰着近 20% 的美国人。为了开发一种成像生物标志物，可以无创地跟踪 OA 进展过程中软骨的结构退化，我们利用 deMRI 来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，代表生物、机械创伤和体内联合治疗，从而产生可重复的退化模式。通过比较 deMRI、定量 MRI (qMRI) 和生物（例如细胞因子）检测，我们将跟踪变性的时间进程并识别从机制上解释 deMRI 变化的关键分子。我们将进一步确定用于早期 OA 检测的 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。在目标 1 中，我们将在体外监测炎症细胞因子和选择性酶如何改变 3D 软骨应变的时空模式。为了解释应变变化，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。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，这将与已知在软骨分解代谢中上调和下调的基因的表达有关。在目标 3 中，我们将比较体内 OA 发病机制动物模型的成像和生化生物标志物。我们将暂时比较 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志物。如果成功，这项工作将为骨科和肌肉骨骼界提供（a）一种临床诊断工具，用于评估在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和利用新兴组织工程进行修复的能力方法，以及（c）更广泛地研究体内承重组织（例如半月板、韧带）机械功能的平台技术。