| Autor: |
Karkampouna S; Department of Molecular Cell Biology, Cancer Genomics Centre and Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands., Kruithof BP; Department of Molecular Cell Biology, Cancer Genomics Centre and Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands., Kloen P; Department of Orthopedic Surgery, Academic Medical Center, Amsterdam, The Netherlands., Obdeijn MC; Department of Plastic, Reconstructive, and Handsurgery, Academic Medical Center, Amsterdam, The Netherlands., van der Laan AM; Department of Molecular Cell Biology, Cancer Genomics Centre and Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands., Tanke HJ; Department of Molecular Cell Biology, Cancer Genomics Centre and Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands., Kemaladewi DU; Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands., Hoogaars WM; Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands., 't Hoen PA; Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands., Aartsma-Rus A; Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands., Clark IM; School of Biological Sciences, University of East Anglia, Norwich Research Park, UK., Ten Dijke P; Department of Molecular Cell Biology, Cancer Genomics Centre and Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands., Goumans MJ; Department of Molecular Cell Biology, Cancer Genomics Centre and Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands., Kruithof-de Julio M; Department of Molecular Cell Biology, Cancer Genomics Centre and Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands. |
| Abstrakt: |
Dupuytren's disease (DD) is a benign fibroproliferative disease of the hand. It is characterized by the excessive production of extracellular matrix (ECM) proteins, which form a strong fibrous tissue between the handpalm and fingers, permanently disrupting the fine movement ability. The major contractile element in DD is the myofibroblast (MFB). This cell has both fibroblast and smooth muscle cell-type characteristics and causes pathological collagen deposition. MFBs generate contractile forces that are transmitted to the surrounding collagen matrix. Μajor profibrotic factors are members of the transforming growth factor-β (TGFβ) pathway which directly regulate the expression levels of several fibrous proteins such as collagen type 1, type 3, and α-smooth muscle actin. Molecular modulation of this signaling pathway could serve as a therapeutic approach. We, therefore, have developed an ex vivo "clinical trial" system to study the properties of intact, patient-derived resection specimens. In these culture conditions, Dupuytren's tissue retains its three-dimensional (3D) structure and viability. As a novel antifibrotic therapeutic approach, we targeted TGFβ type 1 receptor (also termed activin receptor-like kinase 5) expression in cultured Dupuytren's specimens by antisense oligonucleotide-mediated exon skipping. Antisense oligonucleotides targeting activin receptor-like kinase 5 showed specific reduction of ECM and potential for clinical application.Molecular Therapy-Nucleic Acids (2014) 3, e142; doi:10.1038/mtna.2013.69; published online 21 January 2014. |
