Laminin-rich blood vessels display activated growth factor signaling and act as the proliferation centers in Dupuytren’s contracture

Abstract

IntroductionDupuytren’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.MethodsWe 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).ResultsWe 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.ConclusionsBased 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0661-y) contains supplementary material, which is available to authorized users.

Embryonic Stem Cell–like Population in Dupuytren’s Disease

“…4,16 However, what remains unknown is the origin of these cells. 1,2 DD manifests as a nodule through aberrant, uncontrolled proliferation of myofibroblasts 2,16 which progresses to form thick collagenous cords along lines of tension, resulting in fixed flexion contracture of the affected digits with functional loss. 1,2 …”

Connective Tissue Degeneration: Mechanisms of Palmar Fascia Degeneration (Dupuytren’s Disease)

“…Pericytes, the endothelium-covering cells, have been attributed with stem cell properties in several organs [59], which is likely to be the case also in DD fibrosis. Vessel structures that contain high levels of laminins, a key basal membrane component of the connective tissue, facilitate proliferation of myofibroblasts evident by proliferating centres in the vicinity of these vessels [60••]. Endothelial cell and mesenchymal stem cell (MSC)-enriched protein CD105 (type III receptor, endoglin) has been found to be expressed near these proliferation centres.…”

An effectiveness evaluation of the palmar fascia irradiation of patients suffering from Dupuytren’s disease

“…According to recent reports, myofibroblasts play a leading role in the patomechanism of tendon contractures [12,18]. It is suggested that calcium plays a key role not only in the mechanism of myofibroblast contraction, but also in the process of inter-and extracellular signalling [13]. Among other signalling disorders, there is also a Wnt/beta-catenin signalling disruption [11].…”

“…At the end of the physiological process of wound healing, myofibroblasts disappear as a result of apoptosis, yet once the control of this process is impaired, the beneficial processes of remodelling might lead to organ deformity and loss of function [13].…”

“…The occurrence of contractures is related to the disorders of the connective tissue function. Both cells and biochemical substances, such as growth factors and the substances involved in the cellular signalling pathways, take part in this process [10,[13][14][15].…”