Department of Orthopedic Surgery, Harrington Laboratory for Molecular Orthopedics, Kansas City, Kansas, USA.
Department of Medicine, Clinical Immunology and Rheumatology, Kansas City, Kansas, USA.
Gerontology. 2019;65(4):387-396. doi: 10.1159/000496688. Epub 2019 Apr 10.
Aging is a progressive and complicated bioprocess with overall decline in physiological function. Osteoarthritis (OA) is the most common joint disease in middle-aged and older populations. Since the prevalence of OA increases with age and breakdown of articular cartilage is its major hallmark, OA has long been thought of as "wear and tear" of joint cartilage. Nevertheless, recent studies have revealed that changes in the chondrocyte function and matrix components may reduce the material properties of articular cartilage and predispose the joint to OA. The aberrant gene expression in aging articular cartilage that is regulated by various epigenetic mechanisms plays an important role in age-related OA pathogenesis. This review begins with an introduction to the current understanding of epigenetic mechanisms, followed by mechanistic studies on the aging of joint tissues, epigenetic regulation of age-dependent gene expression in articular cartilage, and the significance of epigenetic mechanisms in OA pathogenesis. Our recent findings on age-dependent expression of 2 transcription factors, nuclear factor of activated T cell 1 (NFAT1) and SOX9, and their roles in the formation and aging of articular cartilage are summarized in the review. Chondrocyte dysfunction in aged mice, which is mediated by epigenetically regulated spontaneous reduction of NFAT1 expression in articular cartilage, is highlighted as an important advance in epigenetics and cartilage aging. Potential therapeutic strategies for age-related cartilage degeneration and OA using epigenetic molecular tools are discussed at the end.
衰老是一个渐进且复杂的生物过程，会导致生理功能全面下降。骨关节炎（OA）是中老年人最常见的关节疾病。由于 OA 的患病率随着年龄的增长而增加，而关节软骨的破坏是其主要特征，因此 OA 长期以来一直被认为是关节软骨的“磨损”。然而，最近的研究表明，软骨细胞功能和基质成分的变化可能会降低关节软骨的物质特性，并使关节容易发生 OA。受各种表观遗传机制调控的衰老关节软骨中的异常基因表达在与年龄相关的 OA 发病机制中发挥着重要作用。这篇综述首先介绍了表观遗传机制的当前认识，接着介绍了关节组织老化的机制研究、关节软骨中年龄相关基因表达的表观遗传调控，以及表观遗传机制在 OA 发病机制中的意义。本文总结了我们最近关于转录因子核因子活化 T 细胞 1（NFAT1）和 SOX9 的 2 个依赖性表达的研究结果，及其在关节软骨形成和老化中的作用。软骨细胞功能障碍在衰老小鼠中，由 NFAT1 在软骨细胞中的自发减少介导，这是表观遗传学和软骨老化的一个重要进展。本文最后讨论了使用表观遗传分子工具治疗与年龄相关的软骨退变和 OA 的潜在治疗策略。
