Article

Decorin Is Significantly Overexpressed in Nephrogenic Systemic Fibrosis

Department of Dermatology and Allergology, Ruhr-University Bochum, Bochum, Germany.
American Journal of Clinical Pathology (Impact Factor: 2.51). 07/2009; 132(1):139-43. DOI: 10.1309/AJCPGB55YDURJXZC
Source: PubMed

ABSTRACT

The role of the proteoglycans in the pathogenesis of nephrogenic systemic fibrosis (NSF) is unclear. We assessed expression of decorin, versican, and transforming growth factor beta1 (TGF-beta1) in skin specimens of 10 patients with biopsy-proven NSF and different control groups. Real-time reverse transcription-polymerase chain reaction studies and immunohistochemical analysis were performed on full-thickness skin specimens. The messenger RNA (mRNA) and protein levels of decorin were significantly higher in the skin lesions of patients with NSF than in skin lesions of patients with systemic sclerosis, patients undergoing hemodialysis, and healthy subjects. The versican mRNA levels in NSF lesions differed significantly only from the levels in healthy subjects. TGF-beta1 mRNA expression was significantly overexpressed in NSF lesions compared with control skin specimens investigated. In NSF specimens, the mRNA expression of TGF-beta1 and decorin were highly correlated (r = 0.92). Our results suggest that decorin and TGF-beta1 may have a fundamental role in the pathogenesis of NSF. Conversely, versican seems less likely to be of pathogenetic significance in NSF.

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Available from: Alexander Kreuter, Feb 01, 2016
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    • "Decorin is involved in collagen fibrillogenesis, growth factor modulation, fibrocyte differentiation and cellular growth which may perpetuate fibrosis. The role of decorin in the pathogenesis of NSF was studied by Gambichler et al. [60]. They assessed mRNA expression of decorin, versican and TGF-β in skin specimens of 10 patients with NSF, 16 patients with systemic sclerosis, 8 patients without NSF on hemodialysis and 17 healthy controls. "
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    ABSTRACT: Nephrogenic systemic fibrosis (NSF) is a rare and a debilitating disease noted uncommonly in patients with impaired renal function when exposed to low-stability gadolinium-based contrast agents (Gd-CAs). According to experimental studies, cytokines released by the stimulation of effector cells such as skin macrophages and peripheral blood monocytes activate circulating fibroblasts which play a major role in the development of NSF lesions. The presence of permissive factors, presumably, provides an environment conducive to facilitate the process of fibrosis. Multiple treatment modalities have been tried with variable success rates. More research is necessary to elucidate the underlying pathophysiological mechanisms which could potentially target the initial steps of fibrosis in these patients. This paper attempts to collate the inferences from the in vivo and in vitro experiments to the clinical observations to understand the pathogenesis of NSF. Schematic representations of receptor-mediated molecular pathways of activation of macrophages and fibroblasts by gadolinium and the final pathway to fibrosis are incorporated in the discussion.
    Full-text · Article · Nov 2012
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    • "A resent work showed that the presence of GBCA increases DNA damage in lymphocytes [51]. The presence of high iron and erythropoetin levels are suspected to contribute to the development of NSF as well [44,52-54]. The Gd3+ complexes seem to have an effect on calcium phosphate as a study showed that the calcium phosphate precipitation is increased thus activating macrophages [55]. "
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    ABSTRACT: Nephrogenic Systemic Fibrosis is a rare condition appearing only in patients with severe renal impairment or failure and presents with dermal lesions and involvement of internal organs. Although many cases are mild, an estimated 5% have a progressive debilitating course. To date, there is no known effective treatment thus stressing the necessity of ample prevention measures. An association with the use of Gadolinium based contrast agents (GBCA) makes Nephrogenic Systemic Fibrosis a potential side effect of contrast enhanced magnetic resonance imaging and offers the opportunity for prevention by limiting use of gadolinium based contrast agents in renal failure patients. In itself toxic, Gadolinium is embedded into chelates that allow its safe use as a contrast agent. One NSF theory is that Gadolinium chelates distribute into the extracellular fluid compartment and set Gadolinium ions free, depending on multiple factors among which the duration of chelates exposure is directly related to the renal function. Major medical societies both in Europe and in North America have developed guidelines for the usage of GBCA. Since the establishment of these guidelines and the increased general awareness of this condition, the occurrence of NSF has been nearly eliminated. Giving an overview over the current knowledge of NSF pathobiochemistry, pathogenesis and treatment options this review focuses on the guidelines of the European Medicines Agency, the European Society of Urogenital Radiology, the FDA and the American College of Radiology from 2008 up to 2011 and the transfer of this knowledge into every day practice.
    Full-text · Article · May 2012 · Journal of Cardiovascular Magnetic Resonance
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    • "Whether this switch may also affect the secretion of DCN by peritubular cells (Ungefroren et al., 1995) is not known but in a number of other human fibrotic remodeling processes (e.g. pulmonary and nephrogenic systemic fibrosis ; van Straaten et al., 1999; Fadic et al., 2006; Gambichler et al., 2009), increases in DCN production were reported. What induces the fibrotic remodeling, called a hallmark of human male infertility (De Kretser and Baker, 1996), remains unknown but mast cells (MCs) and macrophages may be involved via their direct and indirect products. "
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    ABSTRACT: Myofibroblastic, peritubular cells in the walls of seminiferous tubules produce low levels of the extracellular matrix (ECM) protein decorin (DCN), which has the ability to interfere with growth factor (GF) signaling. In men with impaired spermatogenesis, fibrotic remodeling of these walls and accumulation of tryptase-positive mast cells (MCs) occur. Human testicular biopsies with normal and focally impaired spermatogenesis (mixed atrophy) were subjected to immunohistochemistry and laser micro-dissection followed by RT-PCR. Primary human testicular peritubular cells (HTPCs), which originate from normal and fibrotically altered testes (HTPC-Fs), were studied by qRT-PCR, western blotting, enzyme-linked immunosorbent assay measurements and Ca(2+) imaging. Phosphorylation and viability/proliferation assays were performed. Immunohistochemistry revealed DCN deposits in the walls of tubules with impaired spermatogenesis. Mirroring the situation in vivo, HTPC-Fs secreted more DCN than HTPCs (P < 0.05). In contrast to HTPCs, HTPC-Fs also responded to the main MC product, tryptase, and to a tryptase receptor (PAR-2) agonist by further increased production of DCN (P < 0.05). Several GF receptors (GFRs) are expressed by HTPCs and HTPC-Fs. DCN acutely increased intracellular Ca(2+)-levels and phosphorylated epidermal GF (EGFR) within minutes. Platelet-derived GF (PDGF) and EGF induced strong mitogenic responses in HTPC/-Fs, actions that were blocked by DCN, suggesting that DCN in the ECM interferes with GF/GFRs signaling of peritubular cells of the human testis. The data indicate that the increase in testicular DCN found in male infertility is a consequence of actions of MC-derived tryptase. We propose that the increases in DCN may consequently imbalance the paracrine signaling pathways in human testis.
    Preview · Article · Jul 2011 · Human Reproduction
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