A role of Wnt signaling in Dupuytren disease, a fibroproliferative disease of the
hand and fingers, has not been fully elucidated. We examined a large set of Wnt pathway
components and signaling targets and found significant dysregulation of 41 Wnt-related
genes in tissue from the Dupuytren nodules compared with patient-matched control tissue.
A large proportion of genes coding for Wnt proteins themselves was downregulated.
However, both canonical Wnt targets and components of the noncanonical signaling pathway
were upregulated. Immunohistochemical analysis revealed that protein expression of
Wnt1-inducible secreted protein 1 (WISP1), a known Wnt target, was increased in nodules
compared with control tissue, but knockdown of WISP1 using small interfering RNA (siRNA)
in the Dupuytren myofibroblasts did not confirm a functional role. The protein expression
of noncanonical pathway components Wnt5A and VANGL2 as well as noncanonical coreceptors
Ror2 and Ryk was increased in nodules. On the contrary, the strongest downregulated
genes in this study were 4 antagonists of Wnt signaling (DKK1, FRZB, SFRP1, and WIF1). Downregulation of these genes in the Dupuytren tissue was mimicked in vitro by
treating normal fibroblasts with transforming growth factor β1 (TGF-β1), suggesting
cross talk between different profibrotic pathways. Furthermore, siRNA-mediated knockdown
of these antagonists in normal fibroblasts led to increased nuclear translocation
of Wnt target β-catenin in response to TGF-β1 treatment. In conclusion, we have shown
extensive dysregulation of Wnt signaling in affected tissue from Dupuytren disease
patients. Components of both the canonical and the noncanonical pathways are upregulated,
whereas endogenous antagonists are downregulated, possibly via interaction with other
profibrotic pathways.
Abbreviations:
cDNA (complementary DNA), Fzd (Frizzled), HDF (human dermal fibroblasts), HPF (high power field), LRP (low-density lipoprotein receptor–related protein), siRNA (small interfering RNA), TGF (transforming growth factor), WISP1 (Wnt1-inducible secreted protein 1)To read this article in full you will need to make a payment
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References
- β-catenin signaling: a novel mediator of fibrosis and potential therapeutic target.Curr Opin Rheumatol. 2011; 23: 562-567
- Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis.Nat Commun. 2012; 3: 735
- Wnt expression is not correlated with beta-catenin dysregulation in Dupuytren's disease.J Negat Results Biomed. 2006; 5: 13
- Beta-catenin overexpression in Dupuytren's disease is unrelated to disease recurrence.Clin Orthop Relat Res. 2009; 467: 838-845
- DNA copy number variations at chromosome 7p14.1 and chromosome 14q11.2 are associated with Dupuytren's disease: potential role for MMP and Wnt signaling pathway.Plast Reconstr Surg. 2012; 129: 921-932
- Whole genome and global expression profiling of Dupuytren's disease: systematic review of current findings and future perspectives.Ann Rheum Dis. 2012; 71: 1440-1447
- Dupuytren disease: anatomy, pathology, presentation, and treatment.J Bone Joint Surg Am. 2007; 89: 189-198
- A systematic review and meta-analysis on the prevalence of Dupuytren disease in the general population of Western countries.Plast Reconstr Surg. 2014; 133: 593-603
- Wnt/β-catenin signaling and disease.Cell. 2012; 149: 1192-1205
- Towards an integrated view of Wnt signaling in development.Development. 2009; 136: 3205-3214
- Wnt signaling and Dupuytren's disease.N Engl J Med. 2011; 365: 307-317
- Beta-catenin expression in Dupuytren's disease: potential role for cell-matrix interactions in modulating beta-catenin levels in vivo and in vitro.Oncogene. 2003; 22: 3680-3684
- Noncanonical WNT-5A signaling regulates TGF-beta-induced extracellular matrix production by airway smooth muscle cells.FASEB J. 2013; 27: 1631-1643
- Sustained β-catenin activity in dermal fibroblasts promotes fibrosis by up-regulating expression of extracellular matrix protein-coding genes.J Pathol. 2015; 235: 686-697
- WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis.J Clin Invest. 2009; 119: 772-787
- WNT1 inducible signaling pathway protein 1 (WISP1): a novel mediator linking development and disease.Int J Biochem Cell Biol. 2011; 43: 306-309
- WISP1, a pro-mitogenic, pro-survival factor, mediates tumor necrosis factor-alpha (TNF-alpha)-stimulated cardiac fibroblast proliferation but inhibits TNF-alpha-induced cardiomyocyte death.J Biol Chem. 2009; 284: 14414-14427
- A role for WNT1-inducible signaling protein-1 in airway remodeling in a rat asthma model.Int Immunopharmacol. 2013; 17: 350-357
- The expression of myoglobin and ROR2 protein in Dupuytren's disease.J Surg Res. 2008; 146: 271-275
- Unique microRNA profile in Dupuytren's contracture supports deregulation of β-catenin pathway.Mod Pathol. 2010; 23: 1544-1552
- Wnt5a secretion stimulated by the extracellular calcium-sensing receptor inhibits defective Wnt signaling in colon cancer cells.Am J Physiol Gastrointest Liver Physiol. 2007; 293: G403-G411
- WNT5A is a regulator of fibroblast proliferation and resistance to apoptosis.Am J Respir Cell Mol Biol. 2009; 41: 583-589
- Anti-apoptotic action of Wnt5a in dermal fibroblasts is mediated by the PKA signaling pathways.Cell Signal. 2008; 20: 1256-1266
- Scientific understanding and clinical management of Dupuytren disease.Nat Rev Rheumatol. 2010; 6: 715-726
- Secreted and transmembrane Wnt inhibitors and activators.Cold Spring Harb Perspect Biol. 2013; 5: a015081
- Tenascin-C downregulates Wnt inhibitor Dickkopf-1, promoting tumorigenesis in a neuroendocrine tumor model.Cell Rep. 2013; 5: 482-492
- Matrix rigidity activates Wnt signaling through down-regulation of Dickkopf-1 protein.J Biol Chem. 2013; 288: 141-151
- The Wnt antagonists DKK1 and SFRP1 are downregulated by promoter hypermethylation in systemic sclerosis.Ann Rheum Dis. 2014; 73: 1232-1239
- Wnt/β-catenin signaling is hyperactivated in systemic sclerosis and induces Smad-dependent fibrotic responses in mesenchymal cells.Arthritis Rheum. 2012; 64: 2734-2745
- SFRP1 reduction results in an increased sensitivity to TGF-β signaling.BMC Cancer. 2011; 11: 59
- Unraveling the signaling pathways promoting fibrosis in Dupuytren's disease reveals TNF as a therapeutic target.Proc Natl Acad Sci U S A. 2013; 110: E928-E937
- Wnt-induced secreted protein 1/CCN4 in liver fibrosis both in vitro and in vivo.Clin Lab. 2014; 60: 29-35
Article info
Publication history
Published online: September 23, 2015
Accepted:
September 17,
2015
Received in revised form:
September 15,
2015
Received:
March 25,
2015
Identification
Copyright
© 2015 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
