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: 10548831
• 负责人: Lin Han
• 金额: $ 33.71万
• 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/10548831
• 关键词: Acceleration; 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; 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; Traumatic Arthropathy; Weight-Bearing state; absorption; aged; aggrecan; cartilage degradation; cartilage regeneration; decorin; design; femur head; improved; in vivo; innovation; mechanical properties; nanomechanics; novel; postnatal; receptor; receptor binding; response

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.

项目总结 新的软骨再生和骨关节炎(OA)治疗方法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认识不完全 其基质组装和生物力学功能。本项目将研究装饰素的活动，一个小的 富含亮氨酸的蛋白多糖(SLRP)，这似乎是关键的集聚糖的组装和稳定性 网络，软骨细胞外基质的主要组成部分。总体目标是确定装饰蛋白在 在健康和退变的软骨中调节聚集素网络的组装。我们的中心假设 核心蛋白聚糖在软骨细胞外基质中起着物理连接物的作用，调节聚集素网络的组装， 这一作用使关节软骨的正常生物力学功能得以建立。 通过增加碎裂的聚集素的滞留，延缓了骨性关节炎的软骨退化。 我们将阐明核心蛋白聚糖在正常软骨细胞外基质组装中的作用(目标1)以及在骨关节炎相关中的作用。 软骨降解(目标2)。在目标1中，我们将首先确定核心蛋白是否对 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，我们将确定是否 核心蛋白聚糖增加了在动态载荷下形成的软骨细胞新基质中聚集素的滞留， 而IF核心蛋白还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 在两种小鼠骨性关节炎模型中，核心蛋白聚糖是否减缓软骨退化和骨性关节炎进展 老年小鼠自然发生的骨性关节炎和创伤后内侧不稳定的骨性骨性关节炎 半月板(DMM)模型。下一步，我们将确定核心蛋白聚糖是否增加了聚集素片段在 退行性软骨，IF核心蛋白也直接影响软骨细胞的分解代谢，以应对炎症 各种因素。将利用一些创新的方法。使用软骨特异的核心蛋白聚糖可诱导的基因敲除 ，我们将描绘正常软骨动态期和进展期的核心蛋白粘附素的活性。 对于办公自动化来说。应用原子力显微镜(AFM)-纳米力学测试，我们将量化机械 装饰素缺乏引起的软骨改变。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及软骨降解中的作用 在骨性关节炎的发病和进展过程中。这项研究的成功完成将建立一种新的结构力学 核心蛋白聚糖介导的聚集素网络在软骨细胞外基质中的组装原理。这将指引我们的未来 通过调节软骨的活性和活性来促进软骨再生和减缓骨性关节炎进展的研究 天然装饰素的可用性，以及装饰素仿生合成分子的设计和交付。