Pain represents a major challenge to modern medicine, as it is often inadequately controlled by currently used analgesics. Recent studies provide evidence that the extracellular matrix (ECM) plays an important role in the development and persistence of pain. Strikingly, chronic pain is one of the most common complaints of patients suffering from genetic alterations affecting the ECM. The Ehlers-Danlos Syndromes (EDS) comprise a heterogeneous group of heritable connective tissue disorders characterized by skin hyperextensibility and fragility, joint hypermobility and generalized connective tissue fragility and is caused by defects in a variety of ECM molecules. With an estimated prevalence of 1:20 00, the classical type of EDS is the most common molecularly explained EDS type, caused by defects in type V collagen. Currently, the mediators and pathways initiating and maintaining pain in EDS are unexplored. Therefore, this proposal aims to characterize the natural history of pain and assess the role of (aberrant) ECM molecules in the generation of chronic pain in classical EDS patients. This will be accomplished through a combination of questionnaires, experimental pain testing as well as state-of-the-art immunohistochemical, transcriptomic and proteomic technologies. Our ultimate goal is to translate insights gained from these studies to improve patient management and develop more effective and safer pain relief for EDS patients and patients with related diseases.