Materials Science and Engineering Program, Department of Mechanical and Aerospace Engineering, University of California, San Diego, CA, USA.
Instituto de Investigación Biomédica de A Coruña, Complexo Hospitalario Universitario de A Coruña, SERGAS, and Universidade da Coruña, A Coruña, Spain.
Osteoarthritis Cartilage. 2017 Nov;25(11):1880-1889. doi: 10.1016/j.joca.2017.07.023. Epub 2017 Aug 8.
Autophagy is a cellular homeostasis mechanism that facilitates normal cell function and survival. Objectives of this study were to determine associations between autophagic responses with meniscus injury, joint aging, and osteoarthritis (OA), and to establish the temporal relationship with structural changes in menisci and cartilage.
Constitutive activation of autophagy during aging was measured in GFP-LC3 transgenic reporter mice between 6 and 30 months. Meniscus injury was created by surgically destabilizing the medial meniscus (DMM) to induce posttraumatic OA in C57BL/6J mice. Levels of autophagy proteins and activation were analyzed by confocal microscopy and immunohistochemistry. Associated histopathological changes, such as cellularity, matrix staining, and structural damage, were graded in the meniscus and compared to changes in articular cartilage.
In C57BL/6J mice, basal autophagy was lower in the meniscus than in articular cartilage. With increasing age, expression of the autophagy proteins ATG5 and LC3 was significantly reduced by 24 months. Age-related changes included abnormal Safranin-O staining and reduced cellularity, which preceded structural damage in the meniscus and articular cartilage. In mice with DMM, autophagy was induced in the meniscus while it was suppressed in cartilage. Articular cartilage exhibited the most profound changes in autophagy and structure that preceded meniscus degeneration. Systemic administration of rapamycin to mice with DMM induced autophagy activation in cartilage and reduced degenerative changes in both meniscus and cartilage.
Autophagy is significantly affected in the meniscus during aging and injury and precedes structural damage. Maintenance of autophagic activity appears critical for meniscus and cartilage integrity.
自噬是一种细胞内稳态机制，有助于正常细胞功能和存活。本研究的目的是确定自噬反应与半月板损伤、关节老化和骨关节炎（OA）之间的关系，并确定与半月板和软骨结构变化的时间关系。
在 GFP-LC3 转基因报告小鼠中，在 6 至 30 个月之间测量衰老过程中自噬的组成性激活。通过手术不稳定内侧半月板（DMM）在 C57BL/6J 小鼠中诱导创伤后 OA 来创建半月板损伤。通过共聚焦显微镜和免疫组织化学分析来分析自噬蛋白和激活水平。在半月板中分析与自噬相关的组织病理学变化，如细胞密度、基质染色和结构损伤，并与关节软骨的变化进行比较。
在 C57BL/6J 小鼠中，半月板中的基础自噬低于关节软骨。随着年龄的增长，自噬蛋白 ATG5 和 LC3 的表达在 24 个月时显着降低。与年龄相关的变化包括异常番红 O 染色和细胞密度降低，这先于半月板和关节软骨的结构损伤。在 DMM 小鼠中，自噬在半月板中被诱导，而在软骨中被抑制。关节软骨中自噬和结构的变化最为明显，先于半月板退变。DMM 小鼠中雷帕霉素的全身给药诱导软骨中自噬的激活，并减少半月板和软骨变性的变化。
自噬在衰老和损伤过程中在半月板中受到显著影响，并先于结构损伤。维持自噬活性对于半月板和软骨完整性似乎至关重要。
