Prevention of Cartilage Degeneration Associated with Meniscal Injury

预防与半月板损伤相关的软骨退变

基本信息

批准号：
7682120
负责人：
RANDY N ROSIER
金额：
$ 39.68万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7682120
关键词：
Acute Address Aging Animal Model Arthritis Arthroscopy Basic Science Bone and Cartilage Funding Cartilage Cartilage injury Cells Chondrocytes Clinical Clinical Research Coix Condition Data Debridement Degenerative polyarthritis Development Diagnostic Disease Disease Progression Evaluation Event Fracture Healing Future Gene Expression Genes Genetic Genetic Models Human Image Immunohistochemistry In Situ Hybridization Inflammatory Injury Interleukin-1 Joints Knee Knock-out Lasers Lead Lesion Link Magnetic Resonance Imaging Matrix Metalloproteinases Measures Medial Membrane Meniscus structure of joint Mesenchymal Methodology Methods Modeling Molecular Mus Operative Surgical Procedures Orthopedics Osteocalcin Outcome Measure PTHLH gene Pathogenesis Pathway interactions Patients Phenotype Polymerase Chain Reaction Prevention Process Proteoglycan Regulation Research Personnel Residual state Role Seminal Signal Pathway Signal Transduction Skeletal system TNF gene Therapeutic Intervention Time Tissues Transcriptional Activation Transforming Growth Factor beta Transgenes Transgenic Mice Translating Trauma Ubiquitin Up-Regulation articular cartilage base bone bone cell bone loss bone morphogenetic protein 6 cytokine disease phenotype functional outcomes gene therapy injury and repair interest novel parathyroid hormone-related protein prognostic programs research study skeletal injury therapeutic target ubiquitin ligase

项目摘要

In the context of orthopaedic trauma, this project proposes to evaluate the relationship between meniscal injury and the development of osteoarthritis (OA). A significant clinical association has been documented between traumatic meniscal injury and OA, but the mechanism(s) behind how damage to the meniscus either directly or indirectly induces pathogenesis are not known. Recently, we have determined that articular chondrocyte loss of TGF-beta signaling induced by over-expression of the ubiquitin ligase Smurf2 leads to an OA-like phenotype in the mouse. Furthermore, we have identified up-regulation of Smurf2 in human articular cartilage shortly following meniscal trauma. Based on these findings, we hypothesize that Smurf2 up-regulation is the seminal event in the arthritic process the follows meniscal injury. Furthermore, based on our findings that increased BMP signaling occurs in conjunction with inappropriate maturation of articular chondrocytes during OA, we also hypothesize that reduction of BMP signaling via genetic or gene therapy approaches will decelerate disease progression in murine OA induced by meniscal injury. To address these central hypotheses, we propose to address the following 3 Specific Aims: In Aim 1, we will comprehensively characterize the tissue and molecular events leading to cartilage degeneration in a model of murine OA induced by meniscal injury. In Aim 2, we will use genetic and gene therapy approaches to evaluate a candidate therapeutic intervention in this murine OA model that are based on reduction of BMP signaling. For these basic science aims, we will employ MRI and microCT imaging methods, histomorphometry and molecular analyses to evaluate disease phenotype. Then, in Aim 3, a human clinical study will be executed which will quantify articular cartilage structural changes following acute meniscal injury using a quantitative MRI approach. Molecular changes will also be assessed in discard cartilage and meniscus tissue to further evaluate the involvement of Smurf2 in the pathogenesis of OA disease following injury.

在骨科创伤的背景下，该项目建议评估半月板之间的关系损伤和骨关节炎（OA）的发展。已记录了显着的临床关联创伤性半月板损伤和 OA 之间的关系，但半月板损伤背后的机制直接或间接诱发发病机制尚不清楚。最近，我们确定了关节泛素连接酶 Smurf2 过度表达诱导软骨细胞丧失 TGF-β 信号传导，导致小鼠中出现类似 OA 的表型。此外，我们还发现人类中 Smurf2 的上调半月板创伤后不久的关节软骨。基于这些发现，我们假设 Smurf2 上调是半月板损伤后关节炎过程中的重要事件。此外，基于我们的研究结果表明，BMP 信号传导的增加与关节的不适当成熟有关。 OA 期间的软骨细胞，我们还假设通过遗传或基因治疗减少 BMP 信号传导方法将减缓由半月板损伤引起的小鼠 OA 的疾病进展。为了解决这些中心假设，我们建议解决以下 3 个具体目标：在目标 1 中，我们将全面描述导致小鼠 OA 模型中软骨退化的组织和分子事件半月板损伤所致。在目标 2 中，我们将使用遗传和基因治疗方法来评估该小鼠 OA 模型中的候选治疗干预基于 BMP 信号传导的减少。为了实现这些基础科学目标，我们将采用 MRI 和 microCT 成像方法、组织形态计量学和分子分析来评估疾病表型。然后，在目标 3 中，将进行人体临床研究这将使用定量方法来量化急性半月板损伤后的关节软骨结构变化 MRI 方法。还将评估废弃软骨和半月板组织的分子变化，以进一步评估 Smurf2 在损伤后 OA 疾病发病机制中的作用。