Biomechanics of Cartilage: Roles of Decorin in ECM Assembly and Degradation

软骨生物力学：核心蛋白聚糖在 ECM 组装和降解中的作用

• 批准号: 10321529
• 负责人: Lin Han
• 金额: $ 33.37万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321529
• 关键词: Adhesions; Aging; Atomic Force Microscopy; Biological; Biological Availability; Biomechanics; Biomimetics; Cartilage; Cartilage Matrix; Catabolism; Cells; Chondrocytes; Collagen; Data; Degenerative polyarthritis; Development; Disease; Event; Experimental Designs; Extracellular Matrix; Future; Growth; Growth Factor; Growth Factor Receptors; Head; Health; Homeostasis; Impairment; In Vitro; Inflammatory; Injury; Insulin-Like Growth Factor I; Interleukin-1 beta; Joints; Knockout Mice; Leucine; Link; Mechanics; Medial meniscus structure; Mediating; Modeling; Molecular; Mus; Operative Surgical Procedures; Pathway interactions; Physiological; Play; Production; Property; Proteoglycan; Role; Signal Transduction; Spectrum Analysis; Structure; Testing; Time; Transforming Growth Factor beta; Weight-Bearing state; absorption; aged; aggrecan; cartilage degradation; cartilage regeneration; decorin; design; improved; in vivo; innovation; mechanical properties; nanomechanics; novel; receptor; receptor binding; response; time use

PROJECT SUMMARY The development of novel cartilage regeneration and osteoarthritis (OA) treatments is limited by our incomplete understanding of how certain molecular activities in cartilage extracellular matrix (ECM) are linked to its matrix assembly and biomechanical functions. This project will study the activities of decorin, a small leucine rich proteoglycan (SLRP), which appears to be critical for the assembly and stability of the aggrecan network, a major constituent of cartilage ECM. The overall objective is to determine the roles of decorin in regulating the assembly of the aggrecan network in healthy and degenerative cartilage. Our central hypothesis is that decorin acts as a “physical linker” to regulate the assembly of the aggrecan network in cartilage ECM, and this role enables the establishment of the normal biomechanical function of cartilage during joint development, and delays cartilage degeneration in OA by increasing the retention of fragmented aggrecan. We will elucidate the roles of decorin in normal cartilage ECM assembly (Aim 1) and in OA-associated cartilage degradation (Aim 2), respectively. In Aim 1, we will first determine whether decorin is essential for the proper biomechanical function of normal cartilage during post-natal growth. Next, we will determine whether decorin increases the retention of aggrecan in the forming neo-matrix of chondrocytes under dynamic loading, and if decorin also regulates chondrocyte anabolic response to growth factors. In Aim 2, we will first determine whether decorin slows down cartilage degradation and OA progression using two murine OA models, including naturally occurring OA in aged mice and injury-induced post-traumatic OA in the destabilization of the medial meniscus (DMM) model. Next, we will determine if decorin increases the retention of aggrecan fragments in degenerative cartilage, and if decorin also directly impacts chondrocyte catabolism in response to inflammatory factors. A number of innovative approaches will be utilized. Using cartilage-specific decorin inducible knockout mice, we will delineate decorin activities during normal cartilage homeostasis and those during the progression of OA. Applying atomic force microscopy (AFM)-nanomechanical tests, we will quantify the mechanical changes of cartilage as a result of decorin deficiency. By combining these approaches, we will elucidate the roles of decorin in regulating the structure and function of normal cartilage, and the degradation of cartilage during OA onset and progression. Successful completion of this study will establish a new structure-mechanics principle of decorin-mediated aggrecan network assembly in the cartilage ECM. This will direct our future studies to improve cartilage regeneration and to slow down OA progression by modulating the activity and availability of native decorin, as well as the design and delivery of decorin-biomimetic synthetic molecules.

项目摘要 新型软骨再生和骨关节炎（OA）治疗的发展受到我们的限制。 对软骨细胞外基质（ECM）中某些分子活性如何联系的不完全理解 它的基质组装和生物力学功能。本项目将研究核心蛋白聚糖的活动，一个小的 富含亮氨酸的蛋白聚糖（SLRP），其似乎对于聚集蛋白聚糖的组装和稳定性至关重要 网络，软骨ECM的主要组成部分。总的目标是确定核心蛋白聚糖在 调节健康和退化软骨中聚集蛋白聚糖网络的组装。我们的核心假设 核心蛋白聚糖作为“物理连接物”调节软骨ECM中聚集蛋白聚糖网络的组装， 这一作用使关节活动过程中软骨的正常生物力学功能得以建立 通过增加碎片聚集蛋白聚糖的保留，延缓OA中的软骨退化。 我们将阐明核心蛋白聚糖在正常软骨细胞外基质组装（Aim 1）和OA相关的细胞外基质中的作用。 软骨降解（Aim 2）。在目标1中，我们将首先确定核心蛋白聚糖是否对于 正常软骨在出生后生长过程中的适当生物力学功能。接下来，我们将确定 核心蛋白聚糖增加了聚集蛋白聚糖在动态负荷下形成的软骨细胞新基质中的保留， 以及核心蛋白聚糖是否也调节软骨细胞对生长因子的合成代谢反应。在目标2中，我们将首先确定 核心蛋白聚糖是否减缓软骨降解和OA进展，使用两种小鼠OA模型，包括 老年小鼠中自然发生的OA和损伤诱导的创伤后OA在内侧 弯月面（DMM）模型。接下来，我们将确定核心蛋白聚糖是否增加聚集蛋白聚糖片段在细胞中的保留。 如果核心蛋白聚糖也直接影响软骨细胞对炎症反应的催化作用， 因素将采用许多创新方法。使用软骨特异性核心蛋白聚糖诱导敲除 在小鼠中，我们将描绘正常软骨稳态和进展过程中的核心蛋白聚糖活性 的OA。应用原子力显微镜（AFM）-纳米力学测试，我们将量化的机械 由于核心蛋白聚糖缺乏而导致的软骨变化。通过结合这些方法，我们将阐明 核心蛋白聚糖在调节正常软骨结构和功能以及软骨降解中的作用 在OA发作和进展期间。成功完成这项研究将建立一个新的结构力学 核心蛋白聚糖介导的聚集蛋白聚糖网络组装在软骨ECM中的原理。这将指引我们的未来 研究通过调节活性来改善软骨再生和减缓OA进展， 天然核心蛋白聚糖的可用性，以及核心蛋白聚糖仿生合成分子的设计和递送。