Further evidence of the involvement of the Wnt signaling pathway in Dupuytren’s disease

Abstract

Genetic background plays an important role in the development of Dupuytren’s disease. A genome-wide association study (GWAS) showed that nine loci are associated with the disease, six of which contain genes that are involved in Wnt signaling (WNT2, WNT4, WNT7B, RSPO2, SFRP4, SULF1). To obtain insight in the role of these genes, we performed expression studies on affected and unaffected patient’s tissues. Surgically obtained nodules and cords from eight Dupuytren’s patients were compared to patient-matched control tissue (unaffected transverse palmar fascia). The Wnt-related genes found in the GWAS, the classical Wnt-downstream protein β-catenin, as well as (myo)fibroblast markers were analyzed using real-time qPCR and immunohistochemical stainings for mRNA levels and protein levels, respectively. The collagen-coding genes COL1A1 and COL3A1 were highly upregulated on mRNA level, both in cords and nodules. Three Wnt-related genes were found to be differently regulated compared to control tissue: WNT2 was downregulated in nodules, WNT7B was upregulated in nodules, and SFRP4 was upregulated in nodules and cords. Immunohistochemistry revealed significantly less staining of Wnt2 in cords, but significantly more staining for Wnt7b in nodules. There was significantly more staining of α-SMA in nodules and cord and β-catenin in nodules than in control tissue. We found differences in expression, both at mRNA and protein level, in several Wnt-related genes found earlier to be associated with Dupuytren’s disease. Of these, Wnt7b was upregulated and found in close association with both α-SMA and β-catenin expressing cells, making it a candidate pro-fibrotic mediator in Dupuytren’s disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s12079-015-0312-8) contains supplementary material, which is available to authorized users.

Active synthesis of type I collagen homotrimer in Dupuytren’s fibrosis is unaffected by anti-TNF-α treatment

“…1 A-C). The results presented are in accordance with previous studies which showed increased COL1A1 mRNA in Dupuytren's tissue compared to unaffected transverse ligament of the palmar aponeurosis (Ten Dam et al, 2016) and increased COL1A1…”

Recent advances in the understanding of Dupuytren’s disease

“…In other organs, downregulation of SFPR4 has been shown to promote myofibroblast activation during fibrosis 18, 19 . These results provide an elegant link between a genetic predisposition to fibrosis in DD and activation of Wnt signalling mediated through SFPR4 13, 16, 17 . Our understanding of the precise role of the genome in the pathogenesis of DD remains incomplete, but it appears that Wnt signalling may be crucial.…”

“…Wnt signalling has been associated with many other fibrotic diseases 14 but this was the first study highlighting this pathway as a potential key pathogenic driver in DD. Since then a number of studies have reported activation of Wnt signalling in DD 15 , including increased expression of the Wnt signalling protein Wnt7b in nodules 16 .…”

Dupuytren’s Contracture

“…In Dupuytren's contracture, this pathway becomes overstimulated leading to fibrosis that invades the dermis resulting in contractures (Evert-Jan, van Beuge, Bank, & Werker, 2016). It is speculated that this process may be T-cell mediated involving the presence of CD3 lymphocytes (Evert-Jan et al, 2016). It is unclear as to whether one single gene is responsible for the development of Dupuytren's contracture or whether the etiology of the disease may be from environmental and/or occupational exposures, especially vibratory exposure, as well (Larsen et al, 2015).…”

“…The Wnt-signaling pathway regulates fibroblast proliferation (Dolmans et al, 2011). In Dupuytren’s contracture, this pathway becomes overstimulated leading to fibrosis that invades the dermis resulting in contractures (Evert-Jan, van Beuge, Bank, & Werker, 2016). It is speculated that this process may be T-cell mediated involving the presence of CD3 lymphocytes (Evert-Jan et al, 2016).…”