Beta-catenin expression in Dupuytren's disease: potential role for cell–matrix interactions in modulating beta-catenin levels in vivo and in vitro

Abstract

Dupuytren's disease (DD) is a superficial fibromatosis of the hand. Although the molecular mechanisms responsible for this disease are unknown, recent studies suggest that beta-catenin may be a key factor involved in fibromatosis. In this study, we analysed the in vivo and in vitro expression levels of beta-catenin in DD, using surgical specimens and primary cell lines. Although no somatic mutations (exon 3) of beta-catenin were detected, Western blot analysis revealed high levels of beta-catenin in diseased palmar fascia, and low to undetectable levels of beta-catenin in patient-matched normal palmar fascia. Immunohistochemistry analysis showed high levels of beta-catenin expression within the disease fascia, as well as cytoplasmic and nuclear accumulations of the protein.Immunoprecipitation of beta-catenin from seven patient lesions showed the protein to be tyrosine phosphorylated. Lastly, Western analysis of three patient-matched (disease and normal fascia) primary cell cultures showed significantly elevated levels of beta-catenin in disease cells cultured in three-dimensional collagen lattices. This is the first extensive in vivo and in vitro characterization of betacatenin in DD, and the first to suggest that the extracellular matrix may play an important role in modulating beta-catenin stability in DD.

SNPs Previously Associated with Dupuytren's Disease Replicated in a North American Cohort

“…Within this pathway, β-catenin is a key signaling molecule regulated by Wnt whose expression is dysregulated in DD. 26,27 Currently, it is unknown how the SNPs affect gene expression within the Wnt pathway. One study demonstrated down-regulation of Wnt11 in surgically removed tissue, 28 and another study demonstrated an increase in Wnt5a, 26 with a third study demonstrating that the microRNA profile in DD is altered, including that for Wnt5a.…”

IGF2 expression and β-catenin levels are increased in Frozen Shoulder Syndrome

“…Increased β-catenin accumulation [17,19] and IGF2 expression [18] have been previously identi ed in DD tissue and primary broblasts compared with controls from adjacent, phenotypically non-brotic palmar fascia. As FSS and DD are clinically associated [3,20], we were interested to see if these characteristics were common to both connective tissue broses.…”

Unique microRNA profile in Dupuytren's contracture supports deregulation of β-catenin pathway

“…Forsman et al 10 associated the upregulation of ROR2 with Dupuytren's contracture pathogenesis for the first time, using the geneexpression data reanalyzed in this study. The catenin (cadherin-associated protein) b-1 (CTNNB1 GeneID: 1499), which has been implicated in Dupuytren's contracture, 27 is the target gene of several miRNAs, but its mRNA-expression level is not altered compared with that of control samples.…”

“…26 Elevated levels of b-catenin have been reported in Dupuytren's contracture without involvement of b-catenin mutations. 27 Possible mechanisms explaining b-catenin accumulation include alterations in the Wnt/b-catenin signaling pathway, which makes it potentially the most important pathway involved in Dupuytren's contracture pathogenesis. This pathway is activated in the wound-healing process, recruiting proliferating fibroblasts to form a collagen matrix, 28 and it has an important function in regulating fibroblast proliferation and cell fate in various fibrous tumors.…”