An integrated proteomics approach for studying the molecular pathogenesis of Dupuytren's disease

Abstract

Dupuytren's disease (DD) is a fibromatosis characterized by non-malignant transformation of palmar fascia leading to permanent contraction of one or more fingers. Despite the extensive knowledge of its clinical pathogenesis, the aetiology of this disease remains obscure. In the present paper, we report for the first time on the proteomic profiling of diseased versus unaffected patient-matched palmar fasciae tissues from DD patients using two-dimensional gel electrophoresis coupled with mass spectrometry analysis. The herein identified proteins were then used to create the protein-protein interaction network (interactome). Such an integrated approach revealed the involvement of several different molecular processes related to DD progression, including extra- and intra-cellular signalling, oxidative stress, cytoskeletal changes, and alterations in cellular metabolism. In particular, autocrine regulation through ERBB-2 and IGF-1R receptors and the Akt signalling pathway have emerged as novel components of pro-survival signalling in Dupuytren's fibroblasts and thus might provide a basis for a new therapeutic strategy in Dupuytren's disease.

Whole genome and global expression profiling of Dupuytren's disease: systematic review of current findings and future perspectives

“…Two whole-proteome studies have been carried out to identify differentially expressed proteins in DD 21 22. While O'Gorman et al 22 identified three potential low molecular weight tissue protein markers that were positively associated with DD, the genes coding for these protein markers were not determined; therefore these findings were not included in this review.…”

“…While O'Gorman et al 22 identified three potential low molecular weight tissue protein markers that were positively associated with DD, the genes coding for these protein markers were not determined; therefore these findings were not included in this review. By comparing biopsies of DD with internal palmar fascia, Kraljevic Pavelic et al 21 have reported 44 genes showing five-fold upregulation in DD through two-dimensional gel electrophoresis. Of these genes, three were reported in mRNA expression profiling microarrays with consistent regulation; ARHGDIA ,8 COL6A3 (meta-analysis) and TPM4 11 .…”

“…Several signalling pathways have been suggested to be involved in DD in published global gene expression or genome-wide association studies, including TGFB signalling,12 Akt signalling21 and Wnt signalling43 (see supplementary table S3, available online only, and figure 3). In addition, genes identified to demonstrate different regulation in this review (from published global gene expression studies and meta-analysis) have been used for pathway enrichment analysis using the KEGG orthology-based annotation system (KOBAs) 2.0, from which pathways associated with integrin from multiple databases were significant (table 2).…”

“…IGF1R and v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (ERBB2) are both involved in the activation of the Akt signalling pathway, and through an integrated proteomic approach were implicated as biomarkers involved in the regulation of cell proliferation in DD 21. Furthermore, POSTN , a gene that has been characterised to be dysregulated in DD in several studies,8 9 11 14 has been suggested to promote metastatic growth of colon cancer by inducing cell survival via the Akt pathway 70.…”

“…Furthermore, POSTN , a gene that has been characterised to be dysregulated in DD in several studies,8 9 11 14 has been suggested to promote metastatic growth of colon cancer by inducing cell survival via the Akt pathway 70. Kraljevic Pavelic et al 21 have also demonstrated upregulated levels of total Akt and phosphorylated Akt in disease fascia when compared with internal control fascia. Activated Akt is involved in the regulation of cell proliferation, survival and metabolism 71.…”