Improving diagnosis and treatment of congenital muscle abnormalities by understanding the activities of irregular connective tissue fibroblasts

我们的目的是确定肢体出生异常，放射状发育不良患者肌肉缺陷的原因，并提高对受影响儿童的诊断和治疗。放射状发育不良，是一种影响手臂致残、毁容的先天缺陷。在受影响的个体中，拇指和桡骨（两个前臂骨中的一个）通常缺失，前臂肌肉异常导致手腕处的手弯曲成“U”形。尽管成熟的外科治疗方法可以稳定手腕关节并使手伸直，但随着儿童的成长，前臂弯曲通常会复发，而且受影响的前臂可能非常短。这对手和手臂的功能有重大影响，可能是终身的，因此对个人和他们的照顾者有巨大的影响。我们正在研究一种鲜为人知的细胞群，称为不规则结缔组织（ICT）成纤维细胞。这些ICT成纤维细胞包围并嵌入形成和成熟的肌肉中，与肌肉形成、修复和疾病有关。肌肉组织不仅仅是肌肉纤维的集合。肌束是肌纤维和这些不规则结缔组织成纤维细胞的复合物，这些成纤维细胞是功能性肌束高度组织结构的关键成分。虽然ICT的重要性已得到公认，但对于它们在肌肉形成过程中的作用以及它们的功能受损如何导致疾病，我们知之甚少。我们正在分析身体细胞周围的“脚手架”，称为细胞外基质（ECM），它是由肌肉ICT成纤维细胞产生的。这种“脚手架”可以在组织形成过程中为细胞提供物理支持和指导，并影响细胞对信号的反应方式。我们有证据表明ICT成纤维细胞通过其对ECM的作用来控制形成肌肉纤维的行为。在成熟的肌肉组织中，ICT细胞产生ECM，形成肌筋膜，这对肌肉组织的完整性至关重要，并使肌纤维收缩产生的力有效地传递给相关的肌腱，从而移动骨骼的骨骼。在初步研究中，我们发现来自RD患者的ICT成纤维细胞分泌一种无组织的ECM，其组成与对照细胞产生的ECM不同。这些差异可以帮助我们解释这种疾病特有的肌肉缺陷。我们还确定了个别RD患者之间的ECM差异，这可以解释为什么某些患者对当前治疗的反应不同。我们已经确定的ECM差异提供了改善RD患者诊断的潜力，作为患者对手术反应的预后指标以及某些手术方法是否值得。所有这些新信息都有助于改善RD的治疗，并可能改善其他组织不能正常发育的疾病的治疗。

We aim to identify the causes of the muscle defects found in patients with the limb birth abnormality, Radial Dysplasia and to improve the diagnosis and treatments that are available to affected children.Radial Dysplasia, is a disabling, disfiguring birth defect affecting the arms. In affected individuals the thumb and radius (one of two forearm bones) are typically missing and abnormal forearm muscles contribute to bending the hand back at the wrist into a 'U' shape. Despite the development of sophisticated surgical treatments to stabilise the wrist joint and straighten the hand, the forearm bowing typically recurs as the child grows, and the affected forearm can be very short. This has a significant effect on hand and arm function, which can be life-long and therefore have an enormous impact on the individual and their carers. We are studying a poorly understood population of cells called irregular connective tissue (ICT) fibroblasts. These ICT fibroblast cells surround, and are embedded within, forming and mature muscles and have been implicated in muscle formation, repair and disease.Muscle tissue is not simply a collection of muscle fibres. A muscle bundle is a composite of muscle fibres and these irregular connective tissue (ICT) fibroblasts, which are critical constituents of the highly organised architecture of a functional muscle bundle. Although the importance of ICT is well established, very little is known about how they act during muscle formation and how their impaired function(s) can lead to disease.We are analysing the 'scaffolding' that surrounds cells of the body, called the extracellular matrix (ECM) that is produced by the muscle ICT fibroblasts. This 'scaffolding' can physically support and guide cells during tissue formation and influence the way cells respond to signals. We have evidence that ICT fibroblasts control the behaviours of forming muscle fibres through their action on the ECM. In mature muscle tissue, ICT cells produce the ECM that forms the muscle fascia that is essential for muscle tissue integrity and enables the force generated by muscle fibre contraction to be efficiently conveyed to the associated tendon and so move the bones of the skeleton.In preliminary studies, we have identified that ICT fibroblasts from RD patients secrete a disorganised ECM that has a different composition to ECM produced by control cells. These differences can help us explain the muscle defects characteristic of the disease. We have also identified ECM differences between individual RD patients that could explain why certain patients respond differently to current treatment. The differences in the ECM we have identified offer the potential to improve diagnosis for RD patients, be prognostic indicators of how well patients will respond to surgery and whether some surgical approaches are worthwhile. All of this new information can help improve treatment of RD and, potentially, other diseases where tissues fail to develop properly.