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John D. Sandy - One of the best experts on this subject based on the ideXlab platform.

  • biochemical identification and immunolocalizaton of aggrecan ADAMTS5 and inter alpha trypsin inhibitor in equine degenerative suspensory ligament desmitis
    Journal of Orthopaedic Research, 2011
    Co-Authors: Anna Plaas, John D. Sandy, Daniel Schenkman, Haowen Liu, Michael A. Diaz, Robert P. Magnus, Paul W. Kopesky, Vincent M. Wang, Courtney Bolambretl, Jorge O. Galante
    Abstract:

    We describe analysis of suspensory ligaments from horses with advanced degenerative suspensory ligament desmitis (DSLD) to identify the major proteoglycans (PGs), ADAMTS-aggrecanases and inter-alpha-trypsin inhibitor (IαI) components associated with ligament degeneration. Specific anatomical regions of suspensory ligaments from two normal horses and four diagnosed with DSLD were analyzed by Western blot and immunohistochemistry for the following: aggrecan, aggrecan fragments, decorin, ADAMTS4, ADAMTS5, and IαI components. When compared to normal, DSLD ligaments showed about a 15-fold increase (P < 0.0014) in aggrecan levels and markedly enhanced staining with Safranin O. The aggrecan was composed of two distinct high molecular weight core protein species. The largest species was found only in DSLD samples and it co-migrated with aggrecan synthesized by equine mesenchymal stem cells (MSC). Many of the DSLD samples also contained abnormally high concentrations of ADAMTS4, ADAMTS5, and IαI. Notably, the ADAMTS5 in DSLD samples, but not normals, was present largely as a high molecular weight complex. We conclude that ligament degeneration in DSLD is associated with matrix changes characteristic of an inflammatory nonhealing wound, specifically containing chondrogenic progenitor cells. Since aggrecan accumulation is a major feature of incomplete healing in tendon and skin of the ADAMTS5 knockout mouse, we propose that ligament failure in DSLD results from a process involving tissue inflammation and the complexation of ADAMTS5.

  • cell death associated ADAMTS4 and versican degradation in vascular tissue
    Journal of Histochemistry and Cytochemistry, 2009
    Co-Authors: Richard D Kenagy, Seung Kee Min, Alexander W Clowes, John D. Sandy
    Abstract:

    High blood flow through baboon polytetrafluorethylene aorto-iliac grafts increases neointimal vascular smooth muscle cell (SMC) death, neointimal atrophy, and cleavage of versican to generate the DPEAAE neoepitope, a marker of ADAMTS-mediated proteolysis. In this study, we have determined the effect of high blood flow on transcript abundance in the neointima for ADAMTS1, -4, -5, -8, -9, -15, and -20. We found that after 24 hr of flow, the mRNA for ADAMTS4 was significantly increased, whereas that for the other family members was unchanged. Because vascular SMC death is markedly increased in the graft after 24 hr of high flow, we next examined the possibility that the ADAMTS4 induction and the cell death are causally related. The addition of Fas ligand to SMC cultures increased both ADAMTS4 mRNA and cell death approximately 5-fold, consistent with the idea that ADAMTS4-dependent cleavage of versican may be partly responsible for cell death and tissue atrophy under these conditions.

  • multimodal signaling by the ADAMTSs a disintegrin and metalloproteinase with thrombospondin motifs promotes neurite extension
    Experimental Neurology, 2008
    Co-Authors: Michelle G Hamel, John D. Sandy, Joanne M Ajmo, Christopher C Leonardo, Fengrong Zuo, Paul E Gottschall
    Abstract:

    Aggregating proteoglycans (PG) bearing chondroitin sulfate (CS) side chains associate with hyaluronan and various secreted proteins to form a complex of extracellular matrix (ECM) that inhibits neural plasticity in the central nervous system (CNS). Chondroitinase treatment depletes PGs of their CS side chains and enhances neurite extension. Increasing evidence from in vivo models indicates that proteolytic cleavage of the PG core protein by members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family of glutamyl-endopeptidases also promotes neural plasticity. The purpose of this study was to determine whether proteolytic action of the ADAMTSs influences neurite outgrowth in cultured neurons. Transfection of primary rat neurons with ADAMTS4 cDNA induced longer neurites, whether the neurons were grown on a monolayer of astrocytes that secrete inhibitory PGs or on laminin/poly-l-lysine substrate alone. Similar results were found when neurons were transfected with a construct encoding a proteolytically inactive, point mutant of ADAMTS4. Addition of recombinant ADAMTS4 or ADAMTS5 protein to immature neuronal cultures also enhanced neurite extension in a dose-dependent manner, an effect demonstrated to be dependent on the activation of MAP ERK1/2 kinase. These results suggest that ADAMTS4 enhances neurite outgrowth via a mechanism that does not require proteolysis but is dependent on activation of the MAP kinase cascade. Thus a model to illustrate multimodal ADAMTS activity would entail proteolysis of CS-bearing PGs to create a loosened matrix environment more favorable for neurite outgrowth, and enhanced neurite outgrowth directly stimulated by ADAMTS signaling at the cell surface.

  • ADAMTS5 mediated aggrecanolysis in murine epiphyseal chondrocyte cultures
    Osteoarthritis and Cartilage, 2006
    Co-Authors: Matthew C Stewart, John D. Sandy, Anna Plaas, Amanda J Fosang, Yun Bai, Barbara Osborn
    Abstract:

    Summary Objective Aggrecan degradation by aggrecanases [a disintegrin and metalloproteinase with thrombospondin-like motifs (ADAMTS) 1, 4, 5, 8, 9, 15] is considered to initiate much of the cartilage pathology seen in human arthritis, however, the proteinase responsible and its mode of control is unclear. The present work was done to examine mechanisms of aggrecanase control in a novel murine epiphyseal cell system and to determine whether ADAMTS5 alone is responsible for aggrecanolysis by these cells. Methods Epiphyseal cells from 4-day-old mice (wild type, TS-5 (−/−), CD44(−/−), syndecan-1(−/−), membrane type-4 matrix metalloproteinase [MT4MMP(−/−)]) were maintained in non-adherent aggregate cultures and aggrecanolysis studied by biochemical and histochemical methods. Confocal immunolocalization analyses were done with specific probes for ADAMTS5, hyaluronan (HA) and aggrecanase-generated fragments of aggrecan. Results Aggrecanolysis by these cells was specifically aggrecanase-mediated and it occurred spontaneously without the need for addition of catabolic stimulators. Chondrocytes from ADAMTS5-null mice were aggrecanase-inactive whereas all other mutant cells behaved as wild type in this regard suggesting that ADAMTS5 activity is not controlled by CD44, syndecan-1 or MT4MMP in this system. Immunohistochemical analysis supported the central role for ADAMTS5 in the degradative pathway and indicated that aggrecanolysis occurs primarily in the HA-poor pericellular region in these cultures. Conclusion These findings are consistent with published in vivo studies showing that single-gene ADAMTS5 ablation confers significant protection on cartilage in murine arthritis. We propose that this culture system and the analytical approaches described provide a valuable framework to further delineate the expression, activity and control of ADAMTS-mediated aggrecanolysis in human arthritis.

  • analysis of ADAMTS4 and mt4 mmp indicates that both are involved in aggrecanolysis in interleukin 1 treated bovine cartilage
    Osteoarthritis and Cartilage, 2005
    Co-Authors: Parth Patwari, John D. Sandy, Gui Gao, Alan J Grodzinsky, Jennifer H Lee
    Abstract:

    Summary Objective To investigate the mechanism of aggrecanolysis in interleukin-1 (IL-1)-treated cartilage tissue by examining the time course of aggrecan cleavages and the tissue and medium content of membrane type 4-matrix metalloproteinases (MT4-MMP) and a disintegrin and metalloproteinase with thrombospondin type I motifs (ADAMTS)4. Methods Articular cartilage explants were harvested from newborn bovine femoropatellar groove. The effects of IL-1 treatment with or without aggrecanase blockade were investigated by Western analysis of aggrecan fragment generation, ADAMTS4 species (p68 and p53), and MT4-MMP, as well as by realtime PCR (polymerase chain reaction) for ADAMTS4 and 5. Aggrecanase was blocked with mannosamine (ManN), an inhibitor of glycosylphosphatidylinositol anchor synthesis, and esculetin (EST), an inhibitor of MMP-1, MMP-3, and MMP-13 gene expression. Results IL-1 treatment caused a major increase in MT4-MMP abundance in the tissue and medium. ADAMTS4 (p68) was abundant in fresh cartilage and this was retained in the tissue in untreated cartilage. IL-1 treatment for 6 days caused a marked loss of p68 from the cartilage and the appearance of p53 in the medium. Addition of either 1.35mM ManN or 31–500μM EST blocked IL-1-mediated aggrecanolysis and this was accompanied by nearly complete inhibition of the MT4-MMP increase, the p68 loss and the formation of p53. IL-1 treatment increased mRNA abundance for ADAMTS4 (∼3-fold) and ADAMTS5 (∼10-fold) but this was not accompanied by a marked change in enzyme protein abundance. Conclusion These studies support a central role for MT4-MMP in IL-1-induced cartilage aggrecanolysis and are consistent with the identification of p68 as the aggrecanase that cleaves within the CS2 domain, and of p53 as the aggrecanase that generates G1-NITEGE. Since the induction by IL-1 was not accompanied by marked changes in total ADAMTS4 protein, but rather in partial conversion of p68 to p53 and release of both from the tissue, we conclude that aggrecanolysis in this model system results from MT4-MMP-mediated processing of a resident pool of ADAMTS4 and release of the p68 and p53 from their normal association with the cell surface.

Suneel S. Apte - One of the best experts on this subject based on the ideXlab platform.

  • identification of novel ADAMTS1 ADAMTS4 and ADAMTS5 cleavage sites in versican using a label free quantitative proteomics approach
    Journal of Proteomics, 2021
    Co-Authors: Daniel R Martin, Salvatore Santamaria, Christopher D Koch, Josefin Ahnstrom, Suneel S. Apte
    Abstract:

    Abstract The chondroitin sulfate proteoglycan versican is important for embryonic development and several human disorders. The versican V1 splice isoform is widely expressed and cleaved by ADAMTS proteases at a well-characterized site, Glu441-Ala442. Since ADAMTS proteases cleave the homologous proteoglycan aggrecan at multiple sites, we hypothesized that additional cleavage sites existed within versican. We report a quantitative label-free approach that ranks abundance of liquid chromatography-tandem mass spectrometry (LC-MS/MS)-identified semi-tryptic peptides after versican digestion by ADAMTS1, ADAMTS4 and ADAMTS5 to identify site-specific cleavages. Recombinant purified versican V1 constructs were digested with the recombinant full-length proteases, using catalytically inactive mutant proteases in control digests. Semi-tryptic peptide abundance ratios determined by LC-MS/MS in ADAMTS:control digests were compared to the mean of all identified peptides to obtain a z-score by which outlier peptides were ranked, using semi-tryptic peptides identifying Glu441 -Ala442 cleavage as the benchmark. Tryptic peptides with higher abundance in control digests supported cleavage site identification. We identified several novel cleavage sites supporting the ADAMTS1/4/5 cleavage site preference for a P1-Glu residue in proteoglycan substrates. Digestion of proteins in vitro and application of this z-score approach is potentially widely applicable for mapping protease cleavage sites using label-free proteomics. Significance Versican abundance and turnover are relevant to the pathogenesis of several human disorders. Versican is cleaved by A Disintegrin-like And Metalloprotease with Thrombospondin type 1 motifs (ADAMTS) family members at Glu441-Ala442, generating a bioactive proteoform called versikine, but additional cleavage sites and the site-specificity of individual ADAMTS proteases is unexplored. Here, we used a label-free proteomics strategy to identify versican cleavage sites for 3 ADAMTS proteases, applying a novel z-score-based statistical approach to compare the protease digests of versican to controls (digests with inactive protease) using the known protease cleavage site as a benchmark. We identified 21 novel cleavage sites that had a comparable z-score to the benchmark. Given the functional significance of versikine, they represent potentially significant cleavages and helped to refine a substrate site preference for each protease.The z-score approach is potentially widely applicable for discovery of site-specific cleavages within an purified protein or small ensemble of proteins using any protease.

  • Determinants of Versican-V1 Proteoglycan Processing by the Metalloproteinase ADAMTS5
    The Journal of biological chemistry, 2014
    Co-Authors: Simon J. Foulcer, Dieter R. Zimmermann, Courtney M Nelson, María T. Dours-zimmermann, Maritza V. Quintero, Balagurunathan Kuberan, J. Larkin, Suneel S. Apte
    Abstract:

    Proteolysis of the Glu(441)-Ala(442) bond in the glycosaminoglycan (GAG) β domain of the versican-V1 variant by a disintegrin-like and metalloproteinase domain with thrombospondin type 1 motif (ADAMTS) proteases is required for proper embryo morphogenesis. However, the processing mechanism and the possibility of additional ADAMTS-cleaved processing sites are unknown. We demonstrate here that if Glu(441) is mutated, ADAMTS5 cleaves inefficiently at a proximate upstream site but normally does not cleave elsewhere within the GAGβ domain. Chondroitin sulfate (CS) modification of versican is a prerequisite for cleavage at the Glu(441)-Ala(442) site, as demonstrated by reduced processing of CS-deficient or chondroitinase ABC-treated versican-V1. Site-directed mutagenesis identified the N-terminal CS attachment sites Ser(507) and Ser(525) as essential for processing of the Glu(441)-Ala(442) bond by ADAMTS5. A construct including only these two GAG chains, but not downstream GAG attachment sites, was cleaved efficiently. Therefore, CS chain attachment to Ser(507) and Ser(525) is necessary and sufficient for versican proteolysis by ADAMTS5. Mutagenesis of Glu(441) and an antibody to a peptide spanning Thr(432)-Gly(445) (i.e. containing the scissile bond) reduced versican-V1 processing. ADAMTS5 lacking the C-terminal ancillary domain did not cleave versican, and an ADAMTS5 ancillary domain construct bound versican-V1 via the CS chains. We conclude that docking of ADAMTS5 with two N-terminal GAG chains of versican-V1 via its ancillary domain is required for versican processing at Glu(441)-Ala(442). V1 proteolysis by ADAMTS1 demonstrated a similar requirement for the N-terminal GAG chains and Glu(441). Therefore, versican cleavage can be inhibited substantially by mutation of Glu(441), Ser(507), and Ser(525) or by an antibody to the region of the scissile bond.

  • cooperation of two ADAMTS metalloproteases in closure of the mouse palate identifies a requirement for versican proteolysis in regulating palatal mesenchyme proliferation
    Development, 2010
    Co-Authors: Hiroyuki Enomoto, Robert P.t. Somerville, Courtney M Nelson, Katrina Mielke, Laura J Dixon, Kimerly A Powell, Suneel S. Apte
    Abstract:

    We have identified a role for two evolutionarily related, secreted metalloproteases of the ADAMTS family, ADAMTS20 and ADAMTS9, in palatogenesis. ADAMTS20 mutations cause the mouse white-spotting mutant belted (bt), whereas ADAMTS9 is essential for survival beyond 7.5 days gestation (E7.5). Functional overlap of ADAMTS9 with ADAMTS20 was identified using ADAMTS9+/–;bt/bt mice, which have a fully penetrant cleft palate. Palate closure was delayed, although eventually completed, in both ADAMTS9+/–;bt/+ and bt/bt mice, demonstrating cooperation of these genes. ADAMTS20 is expressed in palatal mesenchyme, whereas ADAMTS9 is expressed exclusively in palate microvascular endothelium. Palatal shelves isolated from ADAMTS9+/–;bt/bt mice fused in culture, suggesting an intact epithelial TGFβ3 signaling pathway. Cleft palate resulted from a temporally specific delay in palatal shelf elevation and growth towards the midline. Mesenchyme of ADAMTS9+/–;bt/bt palatal shelves had reduced cell proliferation, a lower cell density and decreased processing of versican (VCAN), an extracellular matrix (ECM) proteoglycan and ADAMTS9/20 substrate, from E13.5 to E14.5. Vcan haploinsufficiency led to greater penetrance of cleft palate in bt mice, with a similar defect in palatal shelf extension as ADAMTS9+/–;bt/bt mice. Cell density was normal in bt/bt;Vcanhdf/+ mice, consistent with reduced total intact versican in ECM, but impaired proliferation persisted in palate mesenchyme, suggesting that ADAMTS-cleaved versican is required for cell proliferation. These findings support a model in which cooperative versican proteolysis by ADAMTS9 in vascular endothelium and by ADAMTS20 in palate mesenchyme drives palatal shelf sculpting and extension.

  • ADAMTS 9 is synergistically induced by interleukin 1β and tumor necrosis factor α in oums 27 chondrosarcoma cells and in human chondrocytes
    Arthritis & Rheumatism, 2005
    Co-Authors: Kadir Demircan, Satoshi Hirohata, Tomoko Yonezawa, Suneel S. Apte, Omer Faruk Hatipoglu, Toshitaka Oohashi, Keiichiro Nishida, Yoshifumi Ninomiya
    Abstract:

    Objective To compare induction of the aggrecanases (ADAMTS-1, ADAMTS-4, ADAMTS-5, ADAMTS-8, ADAMTS-9, and ADAMTS-15) by interleukin-1 (IL-1) and tumor necrosis factor (TNF) in chondrocyte-like OUMS-27 cells and human chondrocytes, and to determine the mechanism of induction of the most responsive aggrecanase gene. Methods OUMS-27 cells were stimulated for different periods of time and with various concentrations of IL-1 and/or TNF. Human chondrocytes obtained from osteoarthritic joints and human skin fibroblasts were also stimulated with IL-1 and/or TNF. Total RNA was extracted, reverse transcribed, and analyzed by quantitative real-time polymerase chain reaction and Northern blotting. ADAMTS-9 protein was examined by Western blotting, and the role of the MAPK signaling pathway for ADAMTS9 induction in IL-1-stimulated OUMS-27 cells was investigated. Results IL-1 increased messenger RNA (mRNA) levels of ADAMTS4, ADAMTS5, and ADAMTS9 but not ADAMTS1 and ADAMTS8. The fold increase for ADAMTS9 mRNA was greater than that for mRNA of the other aggrecanase genes. The increase of ADAMTS9 mRNA by IL-1 stimulation was greater in chondrocytes than in fibroblasts. The combination of IL-1 and TNF had a synergistic effect, resulting in a considerable elevation in the level of ADAMTS9 mRNA. ADAMTS-9 protein was also induced in IL-1-stimulated OUMS-27 cells. The MAPK inhibitors SB203580 and PD98059 decreased ADAMTS9 up-regulation in OUMS-27 cells. Conclusion ADAMTS9 is an IL-1- and TNF-inducible gene that appears to be more responsive to these proinflammatory cytokines than are other aggrecanase genes. Furthermore, these cytokines had a synergistic effect on ADAMTS9. Together with the known ability of ADAMTS-9 to proteolytically degrade aggrecan and its potential to cleave other cartilage molecules, the data suggest that ADAMTS-9 may have a pathologic role in arthritis.

Joanne E. Fortune - One of the best experts on this subject based on the ideXlab platform.

  • Progesterone receptor and prostaglandins mediate luteinizing hormone-induced changes in messenger RNAs for ADAMTS proteases in theca cells of bovine periovulatory follicles.
    Molecular reproduction and development, 2017
    Co-Authors: Erin L. Willis, Phillip J. Bridges, Joanne E. Fortune
    Abstract:

    Little is known about the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family of extracellular proteases in ovarian follicles of non-rodent species, particularly in theca cells. In the present study, temporal patterns of change in mRNA for four ADAMTS subtypes and the hormonal transcriptional regulation of two subtypes were investigated in theca cells during the periovulatory period in cattle. Follicles were obtained at 0 h post-gonadotropin-releasing hormone (GnRH; preovulatory) or at 6, 12, 18, or 24 h after injection of GnRH (periovulatory) to induce a luteinizing hormone (LH)/follicle-stimulating hormone surge. ADAMTS1, -2, -7, and -9 transcript abundance were then determined in isolated theca interna. ADAMTS1 and -9 mRNA levels were up-regulated at 24 h post-GnRH; ADAMTS2 mRNA was elevated at 12-24 h post-GnRH; and ADAMTS7 mRNA increased transiently at 12 h post-GnRH compared to other time points. Subsequent in vitro experiments using preovulatory theca interna (0 h post-GnRH) showed that treatment with LH can mimic the observed up-regulation in ADAMTS1 and -9 mRNA and provided evidence that progesterone/progesterone receptor and/or prostaglandins regulate ADAMTS1 and -9 mRNA in theca interna, downstream of the LH surge. Time- and subtype-specific changes in ADAMTS mRNA abundance in vivo, and their regulation in vitro by hormones, argue that ADAMTS family members produced by theca cells play important roles in follicle rupture and the accompanying tissue remodeling in cattle. This article is protected by copyright. All rights reserved

Celik E - One of the best experts on this subject based on the ideXlab platform.

  • Associations between second-trimester amniotic fluid levels of ADAMTS4,
    'Walter de Gruyter GmbH', 2019
    Co-Authors: Melekoglu R, Yilmaz E, Ciftci O, Yt Kafadar, Celik E
    Abstract:

    Background: We investigated the roles of inflammatory cytokines and the A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family in the etiopathogenesis of spontaneous preterm delivery by comparing the ADAMTS4, ADAMTS5, interleukin (IL)-6, and tumor necrosis factor-alpha (TNF-alpha) levels in second-trimester amniotic fluid between pregnant women with preterm birth and term controls.Methods: All pregnant women who underwent second-trimester amniocentesis for genetic analysis between January 1, 2016, and January 1, 2018, were enrolled in this study. From this cohort, 22 patients who subsequently experienced spontaneous preterm delivery before 34 weeks of pregnancy formed the study group, and 22 age- and body mass index (BMI)-matched patients without preterm birth constituted the control group.Results: No significant differences were observed between the preterm birth and control groups in terms of age, BMI, obstetric history of preterm delivery, gestational age at amniocentesis, or indication for amniocentesis. The mean amniotic fluid levels of ADAMTS4 and ADAMTS5 were significantly increased in the preterm birth group compared to the control group (248.3 +/- 22.6 and 182.4 +/- 19.8 pg/mL, P = 0.012; and 198.6 +/- 21.6 and 159.1 +/- 21.7 pg/mL, P = 0.035, respectively). Significantly increased IL-6 and TNF-a levels were also detected in the amniotic fluid of women who experienced spontaneous preterm delivery, relative to controls (142.1 +/- 16.2 and 95.8 +/- 16.4 pg/mL, P < 0.001; and 139.4 +/- 12.5 and 89.6 +/- 11.2 pg/mL, P < 0.001, respectively).Conclusion: The results of this study imply that increased mid-trimester amniotic fluid levels of ADAMTS4, ADAMTS5, IL-6, and TNF-alpha play an important role in the pathophysiology of spontaneous preterm delivery.C1 [Melekoglu, Rauf; Yilmaz, Ercan] Univ Inonu, Fac Med, Dept Obstet & Gynecol, TR-44280 Malatya, Turkey.[Ciftci, Osman] Univ Pamukkale, Fac Med, Dept Med Pharmacol, Denizli, Turkey.[Kafadar, Yusuf Taner] Anamur State Hosp, Clin Obstet & Gynecol, Mersin, Turkey.[Celik, Ebru] Univ Koc, Fac Med, Dept Obstet & Gynecol, Istanbul, Turkey

  • Evaluation of second trimester amniotic fluid ADAMTS4, ADAMTS5, interleukin-6 and tumor necrosis factor-α levels in patients with gestational diabetes mellitus
    'Wiley', 2019
    Co-Authors: Melekoglu R, Yilmaz E, Celik E, Çiftci Osman, Bastemur A.g.
    Abstract:

    Aim: To test the hypothesis that altered A Disintegrin and Metalloproteinase Domains with Thrombospondins motifs (ADAMTS) is implicated in the etiopathogenesis of gestational diabetes mellitus (GDM). Methods: All pregnant women who underwent elective amniocentesis for karyotype analysis between January 1, 2016, and January 1, 2018, were included in this study. From this cohort, the study group consisting of 20 patients diagnosed with GDM was selected and compared against a control group consisting of 20 age- and body mass index (BMI)-matched patients without GDM. ADAMTS4, ADAMTS5, interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels were compared in the second trimester amniotic fluid of patients with GDM and normoglycemic pregnant women. Results: No significant differences were observed between GDM and control groups regarding age, BMI, gestational age at amniocentesis and indication for amniocentesis. Mean amniotic fluid ADAMTS4 and ADAMTS5 levels were significantly increased in the GDM group compared with the control group (253.5 ± 18.7 pg/mL and 188.5 ± 21.3 pg/mL, P < 0.001; 192.9 ± 16.4 pg/mL and 154.8 ± 19.9 pg/mL, P = 0.021, respectively). Significant increases in IL-6 and TNF-α levels were also detected in the amniotic fluid of GDM patients relative to controls (136.2 ± 17.3 pg/mL and 98.3 ± 11.5 pg/mL, P < 0.001; 154.2 ± 12.5 pg/mL and 86.2 ± 10.8 pg/mL, P < 0.001, respectively). Conclusion: The data presented here suggest that increased levels of ADAMTS4, ADAMTS5, IL-6 and TNF-α may play an important role in the progression of GDM. © 2019 Japan Society of Obstetrics and Gynecolog

  • Associations between second-trimester amniotic fluid levels of ADAMTS4, ADAMTS5, IL-6, and TNF-α and spontaneous preterm delivery in singleton pregnancies
    'Walter de Gruyter GmbH', 2019
    Co-Authors: Melekoglu R, Yilmaz E, Ciftci O, Kafadar Y.t., Celik E
    Abstract:

    We investigated the roles of inflammatory cytokines and the A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family in the etiopathogenesis of spontaneous preterm delivery by comparing the ADAMTS4, ADAMTS5, interleukin (IL)-6, and tumor necrosis factor-α (TNF-α) levels in second-trimester amniotic fluid between pregnant women with preterm birth and term controls. All pregnant women who underwent second-trimester amniocentesis for genetic analysis between January 1, 2016, and January 1, 2018, were enrolled in this study. From this cohort, 22 patients who subsequently experienced spontaneous preterm delivery before 34 weeks of pregnancy formed the study group, and 22 age- and body mass index (BMI)-matched patients without preterm birth constituted the control group. No significant differences were observed between the preterm birth and control groups in terms of age, BMI, obstetric history of preterm delivery, gestational age at amniocentesis, or indication for amniocentesis. The mean amniotic fluid levels of ADAMTS4 and ADAMTS5 were significantly increased in the preterm birth group compared to the control group (248.3±22.6 and 182.4±19.8 pg/mL, P=0.012; and 198.6±21.6 and 159.1±21.7 pg/mL, P=0.035, respectively). Significantly increased IL-6 and TNF-α levels were also detected in the amniotic fluid of women who experienced spontaneous preterm delivery, relative to controls (142.1±16.2 and 95.8±16.4 pg/mL, P

  • Associations between second-trimester amniotic fluid levels of ADAMTS4, ADAMTS5, IL-6, and TNF-α and spontaneous preterm delivery in singleton pregnancies.
    'Walter de Gruyter GmbH', 2019
    Co-Authors: Melekoglu R, Yilmaz E, Ciftci O, Celik E
    Abstract:

    Background We investigated the roles of inflammatory cytokines and the A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family in the etiopathogenesis of spontaneous preterm delivery by comparing the ADAMTS4, ADAMTS5, interleukin (IL)-6, and tumor necrosis factor-α (TNF-α) levels in second-trimester amniotic fluid between pregnant women with preterm birth and term controls. Methods All pregnant women who underwent second-trimester amniocentesis for genetic analysis between January 1, 2016, and January 1, 2018, were enrolled in this study. From this cohort, 22 patients who subsequently experienced spontaneous preterm delivery before 34 weeks of pregnancy formed the study group, and 22 age- and body mass index (BMI)-matched patients without preterm birth constituted the control group. Results No significant differences were observed between the preterm birth and control groups in terms of age, BMI, obstetric history of preterm delivery, gestational age at amniocentesis, or indication for amniocentesis. The mean amniotic fluid levels of ADAMTS4 and ADAMTS5 were significantly increased in the preterm birth group compared to the control group (248.3±22.6 and 182.4±19.8 pg/mL, P=0.012; and 198.6±21.6 and 159.1±21.7 pg/mL, P=0.035, respectively). Significantly increased IL-6 and TNF-α levels were also detected in the amniotic fluid of women who experienced spontaneous preterm delivery, relative to controls (142.1±16.2 and 95.8±16.4 pg/mL, P

Kadir Demircan - One of the best experts on this subject based on the ideXlab platform.

  • Expression of ADAMTS2 and ADAMTS5 in the salivary gland of rats after radioiodine therapy.
    Nuclear medicine communications, 2018
    Co-Authors: Murat Sadic, Kadir Demircan, Koray Demirel, Sevil Oskay Halacli, Emre Karakok, Gökhan Koca, Ozgur Ekinci, Meliha Korkmaz
    Abstract:

    OBJECTIVE The aim of this study was to investigate the presence of ADAMTS2 and ADAMTS5 in the salivary gland (SG) of rats after high-dose radioiodine therapy. METHODS A total of 36 male Wistar albino rats were used for this study. Thirty-six male rats were divided randomly into six groups: control and five radioactive iodine (RAI) treatment groups of six rats each. All animals were killed. The evaluation of biodistribution and histopathological studies were carried out on the SGs removed. Real-time PCR and immunohistochemical analysis were carried out to determine mRNA and protein expression levels of ADAMTS genes. Differences between the groups were evaluated statistically. RESULTS In RAI-treated groups, ADAMTS2 and ADAMTS5 gene expression was observed to increase, whereas there was no mRNA or protein expression in the control group. There were statistically significant increases in the mRNA expression of ADAMTS2 (all RAI-administered groups in parathyroid gland and at 4, 24, and 48 h in submandibular gland) and ADAMTS5 (all RAI-administered groups, except on the 30th day in the parathyroid gland and all RAI groups in submandibular gland). Through immunohistochemical analysis, the staining pattern in the extracellular source was also observed in the overexpressed ADAMTS2 and ADAMTS5 groups. Nuclear coarsening and partial focal subnuclei vacuolization were determined in all RAI-administered groups with histopathological examinations. CONCLUSION An increase in the mRNA expression levels of ADAMTS2 and ADAMTS5 genes was detected in the RAI-administered groups. These results suggested that ADAMTS2 and ADAMTS5 genes might play a role in radiation exposure and radioiodine-induced SG changes.

  • differentially regulated ADAMTS1 8 9 and 18 in pancreas adenocarcinoma
    Przeglad Gastroenterologiczny, 2017
    Co-Authors: Murat Ozgur Kilic, Busra Aynekin, Adem Kara, Duygu Icen, Mikdat Bozer, Hacer Haltas, Kadir Demircan
    Abstract:

    Introduction Despite recent diagnostic and therapeutic improvements, pancreas cancer remains one of the highly lethal cancers. The extracellular matrix (ECM) is a physiological barrier that limits the spread of cancer cells into surrounding tissues and distant organs. Disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) is a family of 19 proteases, which is involved in various biological processes such as ECM remodelling and anti-angiogenesis. Aim To investigate the expression of ADAMTS1, 8, 9, and 18 proteinases in pancreas adenocarcinoma and its nodal metastasis. Material and methods The immunostaining status of ADAMTS1, 8, 9, and 18 were investigated in formalin-fixed paraffin-embedded samples of 25 patients who underwent pancreaticoduodenectomy for an adenocarcinoma located at the head of the pancreas. Results In semi-quantitive grading pathologically, ADAMTS1, 8, 9, and 18 were found to be highly stained in all cancerous pancreas samples compared with normal pancreas. In addition, the immune positivity of ADAMTS1, 9, and 18 was found to be higher in metastatic lymph nodes than in non-metastatic lymph tissue. Tumour size was correlated with ADAMTS9 and 18 expressions in cancerous pancreas. Conclusions According to the data obtained from the study, we suggest that these four ADAMTSs may have significant roles in the tumorigenesis and nodal spread of pancreas adenocarcinoma.

  • differentially regulated ADAMTS1 8 and 18 in gastric adenocarcinoma
    Bratislavské lekárske listy, 2017
    Co-Authors: Murat Ozgur Kilic, Busra Aynekin, Adem Kara, Duygu Icen, Kadir Demircan
    Abstract:

    OBJECTIVE The aim is to investigate the expression status of ADAMTS1,8, and 18 proteases in gastric cancer (GC) and lymphatic metastasis. BACKGROUND A disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) is a new protease family, and has important biological functions such as hemostasis, extracellular matrix remodeling and regulation of angiogenesis. METHODS The immunostaining status of ADAMTS1,8, and 18 were investigated in formalin-fixed paraffin-embedded samples of 25 patients who underwent curative resection for GC. RESULTS The immune reactivity scores (IRS) of ADAMTS1, 8, and 18 were significantly higher in the cancerous gastric tissue in comparison to non-cancerous gastric tissue (p < 0.001). In addition, IRS scores of these three ADAMTS proteases were higher in the metastatic lymph nodes compared with healthy lymph nodes (p < 0.001). The expression status of the three ADAMTSs in cancerous gastric tissue was correlated with stage of tumor. Additionally, ADAMTS1 expression and ADAMTS8 expression in cancerous gastric tissue were found to correlate with grade and tumor size, respectively. CONCLUSION This study showed that ADAMTS1, 8, and 18 are highly expressed in GC and its nodal metastases, suggesting  important roles of these proteases in carcinogenesis and lymphatic metastasis. The findings from the present study indicate that these proteases may be promising candidates for novel and alternative treatments in GC (Tab. 3, Fig. 3, Ref. 27).

  • ADAMTS4 5 9 and 15 expressions in the autopsied brain of patients with alzheimer s disease a preliminary immunohistochemistry study
    Klinik Psikofarmakoloji Bulteni-bulletin of Clinical Psychopharmacology, 2016
    Co-Authors: Sultan Pehlivan, Nursel Turkmen Inanir, Filiz Eren, Recep Fedakar, Bulent Eren, Murat Serdar Gurses, Mustafa Numan Ural, Sumeyya Akyol, Suleyman Murat Tagil, Kadir Demircan
    Abstract:

    Objective: Recent studies performed in the central nervous system highlight the pathophysiological relevance of A disintegrin-like and metalloproteinase with thrombospondin motifs (ADAMTS) genes and their protein products. The determination of alterations in expression profiles of ADAMTS family genes in Alzheimer’s disease (AD) patients may contribute to the explanation of tissue pathology and also new ideas for remedial approaches for this incurable but preventable disease. Therefore, the goal of this study was to describe and identify the distribution, characteristics, and any changes in the expression, in other words, immunoreactivity, for aggrecanases (ADAMTS4, 5, 9, and 15) proteins in AD brain. Methods: Nine cases that were autopsied in the Council of Forensic Medicine, Bursa Morgue Department in 2013, were selected. All of the cases were sent for autopsy to the institution within 8 hours after death. At autopsy, tissue samples were obtained for histopathological examination of organs for determining the cause of death. Out of these, two cases were diagnosed with AD by neurologists when they were alive. Immunohistochemical staining was performed on the brain slides by using relevant primary and secondary antibodies against aggrecanase proteins. All images were acquired using a X200 objective of a microscope (Olympus BX53) and evaluated by the staining intensity using a semi-quantitative scoring system. Results: ADAMTS4 and 5 were slightly under-expressed in the brains from autopsied AD cases compared to those of control brains and suggested that extracellular matrix (ECM) degradation was not endorsed in AD brain. On the other hand, ADAMTS9 and 15 aggrecanases were not found to be expressed in correspondent brain sections of AD and control cases. Conclusion: The current study demonstrated that some aggrecanases were found to be under-expressed in AD brains. Additional studies in which all ADAMTS enzymes will be studied in terms of mRNA and protein levels are needed to understand the relative contributions of ADAMTS genes and proteins in AD brains.

  • clinical significance of ADAMTS1 ADAMTS5 ADAMTS9 aggrecanases and il 17a il 23 il 33 cytokines in polycystic ovary syndrome
    Journal of Endocrinological Investigation, 2016
    Co-Authors: Melia Karakose, Kadir Demircan, Esra Tutal, Taner Demirci, Muyesser Sayki Arslan, Mustafa Sahin, Huseyin Tugrul Celik, Fatmanur Hacievliyagil Kazanci, J Karakaya, Erman Cakal
    Abstract:

    Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders among women of reproductive age. A disintegrin and metalloproteinase with thrombospondin-like motifs (ADAMTS) are involved in inflammation and fertility. The aim of this investigation was to evaluate the serum levels of ADAMTS1, ADAMTS5, ADAMTS9, IL-17, IL-23, IL-33 and to find out the relationship between these inflammatory cytokines and ADAMTSs in PCOS patients. A case-control study was performed in a training and research hospital. Eighty patients with PCOS and seventy-eight healthy female volunteers were recruited in the present study. Serum ADAMTS and IL levels were determined by a human enzyme-linked immunoassay (ELISA) in all subjects. The IL-17A, IL-23 and IL-33 levels were significantly higher in the PCOS patients compared to the controls (p < 0.05). We could not find significant difference between the groups in terms of ADAMTS1, ADAMTS5 and ADAMTS9 levels. IL-17A had positive correlations with LDL cholesterol and IL-33 and negative correlations with ADAMTS1, ADAMTS5, and ADAMTS9. IL-33 had positive correlation with LDL cholesterol and IL-17A. In ROC curve analysis, PCOS can be predicted by the use of IL-17A, IL-23 and IL-33 which at a cut-off value of 8.37 pg/mL (44 % sensitivity, 83 % specificity), 26.75 pg/mL (36 % sensitivity, 64 % specificity) and 14.28 pg/mL (83 % sensitivity, 39 % specificity), respectively. The results of the study might suggest that ADAMTS and IL molecules have a role in the pathogenesis of the PCOS. Further efforts are needed to establish causality for ADAMTS-IL axis.