engleski

Using interactomics to unravel molecular pathogenesis of Dupuytren’ s disease

Dupuytren's contracture is a fibromatosis characterized by the non-malignant transformation of palmar fascia that affects between 4 and 20% of the middle-aged and elderly patients in Caucasian populations, with a lower incidence in other populations. Despite its prevalence and the extensive knowledge of its clinical symptoms, the aetiology of Dupuytren’ s contracture remains elusive and the treatment is limited to invasive surgical procedures. In an effort to elucidate the molecular mechanisms underlying the Dupuytren’ s contracture and to potentially provide alternative treatment approaches, we isolated the total protein complement (proteome) of the affected tissue and compared it to the proteome of the unaffected tissue from the same patients. Following the identification of a group of proteins that were differentially expressed in the affected tissue samples, the proteins of interest were organized into an interactome map according to the currently known protein interaction databases. This examination of mutual inter-dependencies among the proteins provided novel insights into the molecular mechanisms of Dupuytren’ s contracture, in particular the mechanisms responsible for proliferation of fibroblasts and their differentiation into myofibroblasts, the implication of oxidative stress as a trigger for the onset of the disease and the cytoskeletal changes that lead to the development of typical clinical symptoms. Furthermore, the structure of the interactome revealed novel molecules involved in the major cell signalling processes in Dupuytren’ s contracture which could function as key mediators of its development. These results were then experimentally validated by Western blot highlighting the potential role of the identified proteins either as novel molecular markers for the disease progression or indicators of the targets for pharmacological treatment. Thus, an analysis of the interactome results not only provided a comprehensive overview of disease processes by putting the proteomics data into a broader biological context, but also revealed molecules that have not been previously implicated in Dupuytren’ s contracture and which would not otherwise be readily identifiable.

Interactom; proteomics; Dupuytren's disease

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