Musculoskeletal tissues ageing: the role of microRNAs and joints homeostasis

随着预计到2020年老年人口将超过6000万(在英国)，肌肉骨骼疾病(MSK)的社会影响正在增加。因此，确定MSK组织与年龄相关的功能恶化的机制是至关重要的。单个MSK组织的恶化可能取决于其他MSK组织的状态，例如关节退化可能受到肌肉无力的影响。控制MSK老化的分子机制仍不清楚，但表观遗传机制被认为发挥了关键作用。microRNAs(MiRs)是基因表达的强大调节者，影响大多数组织的功能，并提供对衰老和环境变化的高通量反应机制(Brown&Goljanek-Whysall，2015)。在衰老过程中，miRs在肌肉、骨骼和软骨中的差异表达已被描述，但其相关性尚未完全了解(Soriano，2016；SteinBush，2017)。我们的数据显示，几个miRs：miR-24、miR-128和miR-34及其靶标在老年小鼠的MSK组织中的表达发生了变化。这些MIR已经被证明或被预测以MSK组织稳态的基本基因为靶点：细胞外基质基因和TGFb信号。我们还表明，miR表达的调节可以改善老年小鼠(人在PREP)的肌肉质量和力量。尽管我们的数据有限，但我们的数据表明，MIR参与了在衰老过程中推动骨关节炎样变化的过程。具体地说，我们已经证明了老年小鼠软骨中miR-199的失调与软骨退行性变有关；在骨关节炎的加载模型中，可以通过关节内注射miR-199模拟/antagomiR来调节这一点(Poulet，2011)。该项目的总体目标是确定中断的miR：靶相互作用是否影响MSK组织衰老，以及基于miR的干预是否有可能改善与肌肉萎缩和类骨关节炎症状相关的年龄相关MSK功能障碍。具体地说，我们将：1.验证选定的miRs及其预测的靶点在骨骼肌、软骨、骨骼中的表达。利用已建立的miR功能获得和丧失方法以及靶基因报道，在体内外研究miR：靶调控网络(S)。建立体外和体内干预对miR：靶相互作用对衰老过程中肌肉骨骼组织动态平衡的影响。

The societal impact of musculoskeletal (MSK) disorders is increasing as the number of older people is predicted to reach over 60 million (in UK) by 2020. It is therefore essential to determine the mechanisms underlying age-related functional deterioration of MSK tissues. It is likely that deterioration of the individual MSK tissue may depend on the state of the other MSK tissues, eg joint degeneration may be affected by muscle weakness. The molecular mechanisms governing MSK ageing are still not understood, however epigenetic mechanisms are thought to play key roles.microRNAs (miRs), robust regulators of gene expression, affect the functionality of most tissues and provide a high-throughput response mechanism to ageing and environmental changes (Brown & Goljanek-Whysall, 2015). Differential expression of miRs in muscle, bone and cartilage has been described during ageing, however the relevance of this is not fully understood (Soriano, 2016; Steinbush, 2017).Our data shows changes in the expression of several miRs: miR-24, miR-128 and miR-34, and their targets in MSK tissues of old mice. These miRs have been shown or are predicted to target fundamental genes for MSK tissue homeostasis: extracellular matrix genes and TGFB signalling. We have also shown that regulation of miR expression improves muscle mass and strength in old mice (man in prep). Although limited, our data indicates the involvement of miRs in driving osteoarthritis-like changes during ageing. Specifically, we have shown that miR-199 dysregulation in cartilage of old mice are associated with cartilage degeneration; this can be modulated using intraarticular injections of miR-199 mimic/antagomiR in the loading model of osteoarthritis (Poulet, 2011).The overall aim of this project is to establish whether disrupted miR:target interactions affect MSK tissue ageing and whether miR-based intervention has the potential to ameliorate age-related MSK dysfunction associated with muscle wasting and OA-like symptoms. Specifically, we will:1. Validate expression of selected miRs and their predicted targets in skeletal muscle, cartilage, bone during ageing.2. Investigate miR:target regulatory network(s) in vitro and in vivo using established miR gain- and loss-of-function approaches and target gene reporters.3. Establish the effects of interventions in vitro and in vivo on miR:target interactions on musculoskeletal tissue homeostasis during ageing.