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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，本项目提出评估半月板的关系