Musculoskeletal tissues ageing: the role of microRNAs and joints homeostasis

肌肉骨骼（MSK）疾病的社会影响正在增加，因为预计到2020年老年人数量将达到6000多万（英国）。因此，确定MSK组织与年龄相关的功能退化机制是必要的。单个MSK组织的恶化可能取决于其他MSK组织的状态，例如关节变性可能受到肌肉无力的影响。调控MSK衰老的分子机制尚不清楚，但表观遗传机制被认为起着关键作用。microRNAs （miRs）是基因表达的强大调节因子，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响应机制（Brown & Goljanek-Whysall, 2015）。在衰老过程中，已经描述了肌肉、骨骼和软骨中miRs的差异表达，但其相关性尚未完全了解（Soriano, 2016; Steinbush, 2017）。我们的数据显示了衰老小鼠MSK组织中miR-24、miR-128和miR-34等miRs及其靶点的表达变化。这些miRs已被证明或预测靶向MSK组织稳态的基本基因：细胞外基质基因和TGFB信号传导。我们还表明，miR表达的调节可以改善老年小鼠的肌肉质量和力量（男性预备）。虽然有限，但我们的数据表明，在衰老过程中，mir参与驱动骨关节炎样变化。具体来说，我们已经表明，miR-199在老年小鼠软骨中的失调与软骨退变有关；这可以在骨关节炎的负荷模型中通过关节内注射miR-199 mimic/antagomiR来调节（Poulet, 2011）。该项目的总体目的是确定miR：靶标相互作用是否会影响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oa样症状相关的年龄相关MSK功能障碍。具体来说，我们将：1。验证在衰老过程中选定的miRs及其预测靶点在骨骼肌、软骨和骨骼中的表达。利用已建立的miR功能获得和功能丧失方法和靶基因报告基因，在体外和体内研究miR：靶调控网络。建立体外和体内干预对miR的影响：衰老过程中肌肉骨骼组织稳态的靶标相互作用。

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.