CHONDROCYTE SUBPOPULATIONS IN AGING AND OSTEOARTHRITIS

骨性关节炎是最常见的关节疾病。尽管衰老是最重要的 骨性关节炎的危险因素，导致衰老相关软骨退变的机制仍有待确定。 特别是，易导致细胞死亡和基质破坏的早期变化没有得到很好的表征。 自噬在细胞内稳态中起着基础性的作用，防止与衰老相关的病理，并扩大 模型生物的寿命。它是以改变和功能障碍为目标的主要生理机制 胞质大分子、膜和细胞器输送到溶酶体进行降解和 回收其成分。在关节软骨中，一种有丝分裂后组织，其特征是非常低的 细胞周转率这一机制似乎对维持正常的细胞功能和 生死存亡。我们的初步结果表明，自噬在结构上是活跃的，并且明显具有保护性。 维持正常软骨内环境平衡的过程。相比之下，软骨老化和骨性关节炎 人类和实验模型与关键的自噬介质ULK1的减少有关， Beclini和Lc3在关节软骨中的表达，并伴随着软骨细胞凋亡的增加。 基于这些发现，我们提出了一种假设，即与年龄相关的和关节损伤导致的抑制 自噬损害了软骨细胞的生存和生物合成能力，导致组织衰竭。 动态平衡和启动骨性关节炎的发病机制。 提出的目标将检验三个具体的假设：(1)软骨老化与异常有关 自噬调节子和自噬通量在特定部位和区域的模式中的表达，这是相关联的 与蛋白质聚集体形成、细胞死亡和基因表达改变有关；(2)实验或衰老相关 软骨细胞自噬调节因子的自发抑制导致生物合成反应异常 和细胞死亡；以及(3)自噬的药理增强通过手术诱导和 与衰老相关的骨性关节炎。 相关性(请参阅说明)： 该项目将为关节衰老和骨性关节炎的关节内稳态机制开辟新的视角。 发病机制。除了检查在已建立的办公自动化中激活的机制外，我们还将解决 在细胞丢失和基质损伤之前的关节内稳态的早期变化。这些研究的结果 有潜力发现保持关节健康的新方法和OA的新治疗目标。

Osteoarthritis (OA) is the most prevalent joint disease. Although aging represents one of the most important risk factors for OA, mechanisms leading to the aging-related cartilage degeneration remain to be determined. In particular, early changes that predispose to cell death and matrix disruption are not well characterized. Autophagy plays a fundamental role in cellular homeostasis, prevents aging-related pathology and extends lifespan In model organisms. It is a major physiological mechanism that targets altered and dysfunctional cytosolic macromolecules, membranes and organelles for delivery to lysosomes for degradation and recycling of its constituents. In articular cartilage, a postmitotic tissue which is characterized by a very low rate of cell turnover this mechanism would appear to be essential to maintain normal cell function and survival. Our preliminary results indicate that autophagy is constitutively active and apparently protective process for the maintenance of homeostasis in normal cartilage. By contrast, cartilage aging and OA in humans and experimental models are associated with a reduction of key autophagy mediators ULK1, Beclini and LC3 in articular cartilage, and this was accompanied by an increase in chondrocyte apoptosis. Based on these findings we propose the hypothesis that 'Aging-related and joint injury-induced inhibition of autophagy compromises chondrocyte survival and biosynthetic capacity, leading to failure of tissue homeostasis and initiating OA pathogenesis.' The proposed aims will test three specific hypotheses: (1) Cartilage aging is associated with abnormal expression of autophagy regulators and autophagy flux in a site and zone specific pattern and this is linked to protein aggregate formation, cell death and altered gene expression; (2) Experimental or aging-related spontaneous inhibition of autophagy regulators in chondrocytes results in abnormal biosynthetic responses and cell death; and (3) Pharmacological enhancement of autophagy ameliorates surgically-induced and aging-related OA. RELEVANCE (See instructions): This project will open new perspectives on mechanisms of joint homeostasis in joint aging and OA pathogenesis. In addition to examining mechanisms that are activated in established OA we will address early changes in joint homeostasis that precede cell loss and matrix damage. Results from these studies have potential to discover new approaches to maintain joint health and new therapeutic targets for OA.