FoxO Transcription Factors in Spine Aging and Disease

摘要 腰痛是最常见的肌肉骨骼疾病，也是导致残疾的主要原因。这 昂贵的条件影响骨骼和软组织的脊椎和主要的根本原因是 椎间盘退变（IVD）。衰老是IVD变性（IDD）的主要风险因素。 IVD细胞和细胞外基质中的血管紧张素相关变化被认为会损害组织 体内平衡并触发IDD的发作。然而，潜在的精确分子机制 IDD没有得到很好的理解。Forkhead box O（FoxO）转录因子在进化上是 与长寿和细胞内稳态有关的保守基因。FoxO表达失调 和活动与几种与年龄有关的疾病有关。我们已经报道了FoxO蛋白 支持抗氧化应激和促进人关节软骨细胞自噬，和 在老化和骨关节炎期间，关节软骨中FoxO的表达减少。我们的初步 研究表明，FoxO表达在老年小鼠的IVD和终板中减少， col 2a 1cre驱动的FoxO缺失表现出IVD的异常组织化和肥大 和软骨终板这些观察结果支持了一个假设，即FoxO是重要的 IVD中FoxO表达的减少是IVD中FoxO表达的早期事件， 最终导致IVD退化在目的1中，我们将测量人骨髓中FoxO的表达。 和小鼠IVD在整个广泛的老化谱和不同程度的退化，我们 将FoxO表达的变化与IVD的组织病理学变化以及已知的 IDD的媒介。在目的2中，我们将通过分析FoxO在体内脊柱中的作用来研究FoxO在体内脊柱中的作用。 在具有以下特征的聚集蛋白聚糖-CreERT 2-FoxOfl/fl小鼠的IVD中的自发组织学和分子学变化： 出生后，组织特异性缺失FoxO。拟议的项目将证明以下原则： 与年龄相关的FoxO表达减少是IDD发病机制中的早期和关键事件。这 将为旨在调节FoxO表达和/或 预防年龄相关和损伤诱导的IVD变性的活性。

ABSTRACT Low back pain is the most common musculoskeletal disease and a major cause of disability. This costly condition affects bone and soft tissues of the spine and the principal underlying cause is degeneration of the intervertebral disc (IVD). Aging is a main risk factor for IVD degeneration (IDD). Age-related changes in the IVD cells and extracellular matrix are thought to compromise tissue homeostasis and trigger the onset of IDD. However, the precise molecular mechanisms underlying IDD are not well understood. The Forkhead box O (FoxO) transcription factors are evolutionarily conserved genes implicated in longevity and cellular homeostasis. Dysregulated FoxO expression and activity has been linked to several age-related diseases.. We have reported that FoxO proteins support resistance to oxidative stress and promote autophagy in human articular chondrocytes, and that FoxO expression is reduced in articular cartilage during aging and osteoarthritis. Our preliminary studies show that FoxO expression is reduced in IVD and endplates of aged mice and that in mice with col2a1cre-driven deletion of FoxO manifest abnormal organization and hypertrophy of the IVD and the cartilaginous endplates. These observations support hypothesis is that FoxO are important factors controlling IVD homeostasis and that a reduction of FoxO expression in IVD is an early event that eventually leads to IVD degeneration. In Aim 1 we will measure the expression of FoxO in human and mouse IVD throughout a broad aging spectrum and different degrees of degeneration, and we will correlate changes in FoxO expression with histopathological changes in IVD and with known mediators of IDD. In Aim 2 we will examine the role of FoxO in spine in vivo by analyzing spontaneous histological and molecular changes in the IVD of aggrecan-CreERT2 -FoxOfl/fl mice with postnatal, tissue-specific deletion of FoxO. The proposed project will establish proof of principle that aging-related reduction in FoxO expression is an early and critical event in IDD pathogenesis. This will provide the foundation for therapeutic approaches aimed at modulating FoxO expression and/or activity to prevent age-related and injury-induced IVD degeneration.