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Background: Pseudoxanthoma elasticum (PXE) is a rare hereditary disorder predominantly affecting the skin, the eyes and the cardiovascular system. The disease is caused by mutations in the ABCC6 gene and characterized by ectopic calcification and extracellular matrix (ECM) alterations. Matrix metalloproteinases (MMPs) play a pivotal role in the process of ECM remodeling and are likely implied in PXE pathology. The aim of the present study was to investigate the association of single nucleotide polymorphisms (SNPs) in the promoter of the MMP2 gene, and PXE., Methods: We evaluated the allelic distribution of five SNPs in the MMP2 promoter in DNA samples from 168 German patients affected by PXE and in 168 healthy, age- and sex-matched control subjects using restriction fragment length polymorphism analysis., Results: The alleles c.-1575G, c.-1306C, and c.-790T were more abundant in the PXE patients' group. Furthermore, the haplotype GCTCG was significantly associated with PXE (OR 1.56, 95% CI 1.14-2.12, P(corrected)=0.026)., Conclusions: Our results may indicate an involvement of MMP2 in the pathology of PXE. The promoter polymorphisms associated with PXE may lead to increased MMP2 expression and thereby contribute to the elevated proteolytic activity observed in PXE in vitro and in vivo., (Copyright 2010 Elsevier B.V. All rights reserved.)

Background: We investigated the xylosyltransferase (XT) activity in the serum of liver fibrotic patients with hepatitis C virus induced liver fibrosis at different stages as determined according to the scoring system of Desmet and Scheuer., Methods: Measurement of XT activity was performed by liquid chromatography-tandem mass spectrometry., Results: We found that serum XT activity in males (n=59, median+/-SD, 27.2+/-2.8 mU/L, p<0.001) and females (n=54, 23.6+/-3.0 mU/L, p<0.01) with liver fibrosis is significantly elevated in comparison to a corresponding healthy control cohort of males (n=50, 23.9+/-2.8 mU/L) and females (n=52, 21.5+/-3.7 mU/L), respectively. Of note, independent from gender, serum XT activity positively correlated with the stage of fibrosis but declined again in patients with histologically proven cirrhosis., Conclusions: XT activity is increased in the serum of patients with liver fibrosis at different stages, pointing to a possible pathogenetic role in elevated proteoglycan biosynthesis in fibrotic remodeling of this organ during chronic injury.

Background: Proteoglycans are major components of the glomerular basement membrane, being responsible for their permeability properties. Type 1 diabetic patients have an altered proteoglycan metabolism, which contributes to microvascular complications like diabetic nephropathy. Xylosyltransferase II (XT-II) is a chain-initiating enzyme in the biosynthesis of basement membrane proteoglycans and catalyzes the transfer of xylose to selected serine residues in the core protein. Thus, genetic variations in the XT-II coding gene XYLT2 might be implicated in the initiation and progression of late diabetic complications., Methods: Genotyping of 6 genetic variations in the XYLT2 gene and haplotype analysis was performed in 697 type 1 diabetic patients (358 with and 338 without diabetic nephropathy)., Results: The haplotype analysis of 6 XYLT2 polymorphisms revealed one haplotype (GATTCG) to be significantly less frequent among type 1 patients with diabetic nephropathy (p=0.002, OR=0.13, 95% CI=0.03-0.59). The haplotype GATTCG consist of the XYLT2 variations c.166G>A, c.177A>G, c.342T>C, IVS6-9T>C, c.1569C>T and c.2402C>G. No genotype-phenotype interactions were revealed., Conclusions: Our data show that a XYLT2 haplotype is associated with nephropathy in type 1 diabetic patients.

Background: Pseudoxanthoma elasticum (PXE, OMIM 177850 and 264800) is a rare heritable disorder predominantly affecting the skin, the eyes and the vascular system. The disease is caused by mutations in the ABCC6 gene and is characterized by calcification and extracellular matrix remodeling, including alterations of the vessel walls. Here, we investigated the cell adhesion molecules ICAM-1 in PXE patients., Methods: Soluble ICAM-1 was determined in 58 non-consanguineous PXE patients by quantitative sandwich enzyme immunoassay. The allelic frequencies of the ICAM-1 variant p.K469E were analyzed in patients and age- and sex-matched controls., Results: Soluble ICAM-1 levels were significantly elevated in male and female PXE patients (p<0.02 and p<0.001, respectively). In addition, the ICAM-1 concentration correlated with the ABCC6 gene status of the PXE patients. The ICAM variant p.K469E genotypes were not different in PXE patients and age- and sex-matched controls., Conclusions: Our data show for the first time increased ICAM-1 concentrations in PXE patients, potentially due to the chronic oxidative stress and elevated protease activity followed by extracellular matrix remodeling which have been previously observed in PXE patients.

Background: The formation of abdominal aortic aneurysm (AAA) is caused by a destructive remodeling of the extracellular matrix in the vascular wall. Proteoglycan content and biosynthesis have been shown to be altered in AAA. Xylosyltransferase I (XT-I) is the initial and rate-limiting enzyme in the biosynthesis of the proteoglycan-linked glycosaminoglycan chains. A familial predisposition to AAA is well recognized. Thus, variations in the XT-I coding gene XYLT1 might be risk factors for AAA formation., Methods: We performed genotyping of two genetic variations in the XYLT1 gene which, have been already linked to proteoglycan-associated diseases, in 129 AAA patients and 129 age- and sex-matched healthy controls., Results: The T-allele of the polymorphism c.343G>T (p.A115S) was found to be significantly more frequent in AAA patients compared to the healthy control group, demonstrating that carriers of the T-allele have a 5-fold increased risk of developing AAA (odds ratio 4.87, 95%-CI 1.38-17.19; p=0.011)., Conclusions: Our results show that XT-I polymorphisms potentially confer to the genetic susceptibility of AAA.

Background: Tissue factor pathway inhibitor (TFPI) is a multivalent Kunitz-type serine proteinase inhibitor which plays a central role in the extrinsic pathway of blood coagulation. A significant role of TFPI for the follicular development has been discussed in recent studies, and thrombotic complications during IVF procedure are a common problem. To elucidate the pathophysiological mechanisms underlying these problems, we have measured TFPI levels in human follicular fluid (hFF) of women undergoing in vitro fertilisation (IVF)., Methods: Total TFPI concentrations were determined in hFF of 28 women undergoing IVF treatment, 6 of whom developed an ovarian hyperstimulation syndrome (OHSS)., Results and Conclusions: This is the first study to demonstrate an age-dependance of TFPI concentrations in hFF. Additionally, TFPI levels in hFF of women developing OHSS were determined as 323+/-66.8 ng/mL (mean+/-SD) in comparison with 279+/-137 ng/mL for non-OHSS patients. Our findings demonstrate that, unlike the decreased TFPI levels found in OHSS patients' blood, there is no statistically significant difference in hFF TFPI levels between OHSS and non-OHSS patients. Furthermore, we could show that the outcome of the IVF procedure is not correlated with TFPI levels in hFF.

Background: Proteoglycans play an important role during the mammalian conception process and are functionally involved in the preservation of the sperm motility and velocity. Human xylosyltransferase (EC 2.4.2.26, XT) is the initial enzyme involved in the biosynthesis of the glycosaminoglycan chains in proteoglycans. XT activity in body fluids was shown to be an indicator for the actual proteoglycan biosynthesis rate., Methods: Xylosyltransferase activity was determined in seminal plasma and serum samples of 50 healthy semen donors, 20 infertile men with oligo-, astheno- or teratozoospermia and men after vasectomy. For identification of the XT secreting glands split ejaculates were analyzed., Results: XT activity in seminal plasma samples of infertile men was significantly reduced (mean 1.53 mU/l, 90% range 0.95-2.52 mU/l, p<0.05) in comparison to healthy donors (mean 3.21 mU/l, 90% range 1.82-4.65 mU/l). The analysis of the fractionated ejaculates revealed that the highest XT activity was found in portions secreted by the seminal vesicle glands., Conclusions: In view of the increasing interest for in vitro fertilization, monitoring the seminal plasma XT activity of men with unexplained infertility is proposed to be an advantageous additional biochemical parameter that could be useful for improving the methods producing pregnancy in some couples.