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

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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.