Prevention of Cartilage Degeneration Associated with Meniscal Injury

预防与半月板损伤相关的软骨退变

• 批准号: 7891425
• 负责人: RANDY N ROSIER
• 金额: $ 45.55万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7891425
• 关键词: Acute; Address; Aging; Animal Model; Arthritis; Arthroscopy; Basic Science; Caring; Cartilage; Cartilage injury; Cells; Chondrocytes; Clinical; Clinical Research; Coix; Data; Debridement; Degenerative polyarthritis; Development; Diagnostic; Disease; Disease Progression; Evaluation; Event; Fracture Healing; Future; Gene Expression; Genes; Genetic; 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; Modeling; Molecular; Molecular Genetics; Mus; Operative Surgical Procedures; Orthopedics; Osteocalcin; Outcome Measure; Pathogenesis; Pathway interactions; Patients; Phenotype; Prevention; Process; Proteoglycan; Regulation; Research Personnel; Residual state; Role; Seminal; Signal Pathway; Signal Transduction; TNF gene; Therapeutic Intervention; Time; Tissues; 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; imaging modality; injury and repair; interest; novel; parathyroid hormone-related protein; prognostic; programs; research study; skeletal; skeletal injury; therapeutic target; ubiquitin ligase

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，本项目建议评估半月板之间的关系 损伤与骨关节炎(OA)的发展。一个重要的临床关联已被记录在案 创伤性半月板损伤与骨性关节炎之间的关系，但半月板损伤背后的机制(S) 无论是直接还是间接诱导发病机制尚不清楚。最近，我们确定了关节 泛素连接酶SMurf2过表达导致软骨细胞失去转化生长因子-β信号转导 小鼠的一种类似骨关节炎的表型。此外，我们还发现人类中SMurf2的表达上调 半月板损伤后不久的关节软骨。基于这些发现，我们假设蓝精灵2 在半月板损伤后的关节炎过程中，表达上调是一个重要事件。此外，基于 我们的研究发现，BMP信号的增加与关节的不成熟有关 在骨关节炎过程中，我们还假设BMP信号通过基因或基因治疗而减少 治疗方法将减缓半月板损伤所致的小鼠骨性关节炎的病情进展。要解决这些问题 中心假设，我们建议解决以下三个具体目标：在目标1中，我们将全面 在小鼠骨性关节炎模型中表征导致软骨退变的组织和分子事件 由半月板损伤引起。在目标2中，我们将使用遗传和基因治疗方法来评估 在这个基于BMP信号减少的小鼠骨关节炎模型中，候选的治疗干预。 对于这些基本的科学目标，我们将使用MRI和MicroCT成像方法，组织形态计量学和 用于疾病表型评估的分子分析。然后，在目标3中，将执行人体临床研究 它将量化急性半月板损伤后关节软骨的结构变化 核磁共振检查。还将评估丢弃的软骨和半月板组织中的分子变化，以进一步 探讨SMurf2在创伤后骨性关节炎发病机制中的作用。