Novel Ex Vivo Culture Method for the Study of Dupuytren's Disease: Effects of TGFβ Type 1 Receptor Modulation by Antisense Oligonucleotides.
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.
Department of Molecular Cell Biology, Cancer Genomics Centre and Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Sofia
S
Karkampouna
Department of Molecular Cell Biology, Cancer Genomics Centre and Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Boudewijn Pt
BP
Kruithof
Department of Orthopedic Surgery, Academic Medical Center, Amsterdam, The Netherlands.
Peter
P
Kloen
Department of Plastic, Reconstructive, and Handsurgery, Academic Medical Center, Amsterdam, The Netherlands.
Miryam C
MC
Obdeijn
Department of Molecular Cell Biology, Cancer Genomics Centre and Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Annelies Ma
AM
van der Laan
Department of Molecular Cell Biology, Cancer Genomics Centre and Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Hans J
HJ
Tanke
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Dwi U
DU
Kemaladewi
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Willem Mh
WM
Hoogaars
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Peter Ac
PA
't Hoen
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Annemieke
A
Aartsma-Rus
School of Biological Sciences, University of East Anglia, Norwich Research Park, UK.
Ian M
IM
Clark
Department of Molecular Cell Biology, Cancer Genomics Centre and Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Peter
P
Ten Dijke
Department of Molecular Cell Biology, Cancer Genomics Centre and Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Marie-José
MJ
Goumans
Department of Molecular Cell Biology, Cancer Genomics Centre and Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Marianna
M
Kruithof-de Julio