title: Laminin-rich blood vessels display activated growth factor signaling and act as the proliferation centers in Dupuytren's contracture.
abstract: BACKGROUND
  Dupuytren's contracture (DC) is a chronic fibroproliferative disease of the hand, which is characterized by uncontrolled proliferation of atypical myofibroblasts at the cellular level. We hypothesized that specific areas of the DC tissue are sustaining the cell proliferation and studied the potential molecular determinants that might contribute to the formation of such niches.
  
  
  METHODS
  We studied the expression pattern of cell proliferation marker Ki67, phosphorylated AKT (Ak mouse strain thymoma) kinase, DC-associated growth factors (connective tissue growth factor (CTGF), basic fibroblast growth factor (bFGF), insulin-like growth factor 2 (IGF-2)) and extracellular matrix components (laminins, fibronectin, collagen IV) in DC tissue and normal palmar fascia using immunofluorescence microscopy and quantitative real-time polymerase chain reaction (qPCR).
  
  
  RESULTS
  We found that proliferative cells in the DC nodules were concentrated in the immediate vicinity of small blood vessels and localized predominantly in the myofibroblast layer. Correspondingly, the DC-associated blood vessels contained increased levels of phosphorylated AKT, a hallmark of activated growth factor signaling. When studying the expression of potential activators of AKT signaling we found that the expression of bFGF was confined to the endothelium of the small blood vessels, IGF-2 was present uniformly in the DC tissue and CTGF was expressed in the DC-associated sweat gland acini. In addition, the blood vessels in DC nodules contained increased amounts of laminins 511 and 521, which have been previously shown to promote the proliferation and stem cell properties of different cell types.
  
  
  CONCLUSIONS
  Based on our findings, we propose that in the DC-associated small blood vessels the presence of growth factors in combination with favorable extracellular matrix composition provide a supportive environment for sustained proliferation of myofibroblasts and thus the blood vessels play an important role in DC pathogenesis.
authors.affiliation: Institute of Molecular and Cell Biology, University of Tartu, Riia 23, 51010, Tartu, Estonia. janeli.viil@ut.ee.
authors.forename: Janeli
authors.initials: J
authors.lastname: Viil
authors.affiliation: Department of Traumatology and Orthopedics, Tartu University Hospital, Puusepa 8, 51014, Tartu, Estonia. katre.maasalu@kliinikum.ee.|Clinic of Traumatology and Orthopedics, Tartu University Hospital, Puusepa 8, 51014, Tartu, Estonia. katre.maasalu@kliinikum.ee.
authors.forename: Katre
authors.initials: K
authors.lastname: Maasalu
authors.affiliation: Institute of Molecular and Cell Biology, University of Tartu, Riia 23, 51010, Tartu, Estonia. kristina902@gmail.com.
authors.forename: Kristina
authors.initials: K
authors.lastname: Mäemets-Allas
authors.affiliation: Institute of Molecular and Cell Biology, University of Tartu, Riia 23, 51010, Tartu, Estonia. liis.tamming@gmail.com.
authors.forename: Liis
authors.initials: L
authors.lastname: Tamming
authors.affiliation: Institute of Molecular and Cell Biology, University of Tartu, Riia 23, 51010, Tartu, Estonia. kadil6hmussaar@gmail.com.
authors.forename: Kadi
authors.initials: K
authors.lastname: Lõhmussaar
authors.affiliation: Institute of Molecular and Cell Biology, University of Tartu, Riia 23, 51010, Tartu, Estonia. mikktooming@gmail.com.
authors.forename: Mikk
authors.initials: M
authors.lastname: Tooming
authors.affiliation: Institute of Molecular and Cell Biology, University of Tartu, Riia 23, 51010, Tartu, Estonia. suling@ebc.ee.
authors.forename: Sulev
authors.initials: S
authors.lastname: Ingerpuu
authors.affiliation: Department of Traumatology and Orthopedics, Tartu University Hospital, Puusepa 8, 51014, Tartu, Estonia. aare.martson@kliinikum.ee.|Clinic of Traumatology and Orthopedics, Tartu University Hospital, Puusepa 8, 51014, Tartu, Estonia. aare.martson@kliinikum.ee.
authors.forename: Aare
authors.initials: A
authors.lastname: Märtson
authors.affiliation: Institute of Molecular and Cell Biology, University of Tartu, Riia 23, 51010, Tartu, Estonia. viljar.jaks@ut.ee.|Department of Biosciences and Nutrition, Karolinska Institutet, Hälsovägen 7, 141 83, Huddinge, Sweden. viljar.jaks@ut.ee.
authors.forename: Viljar
authors.initials: V
authors.lastname: Jaks
mesh_terms: D001808:Blood Vessels / Q000378:metabolism*; D049109:Cell Proliferation; D004387:Dupuytren Contracture / Q000378:metabolism / Q000473:pathology*; D005205:Fascia / Q000098:blood supply / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D007797:Laminin