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Arning, Astrid, Astrid Jeibmann, Stephan Köhnemann, et al. "ADAMTS genes and the risk of cerebral aneurysm." Journal of Neurosurgery 125, no. 2 (2016): 269–74. http://dx.doi.org/10.3171/2015.7.jns154.
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OBJECTIVE Cerebral aneurysms (CAs) affect 2%–5% of the population, and familial predisposition plays a significant role in CA pathogenesis. Several lines of evidence suggest that genetic variations in matrix metalloproteinase genes (MMP) are involved in the etiopathology of CAs. The authors performed a case-control study to investigate the effect of 4 MMP variants from the ADAMTS family on the pathogenesis of CAs. METHODS To identify susceptible genetic variants, the authors investigated 8 single nucleotide polymorphisms (SNPs) in 4 genes from the ADAMTS family (ADAMTS2, -7, -12, and -13) known to be associated with vascular diseases. The study included 353 patients with CAs and 1055 healthy adults. RESULTS The authors found significant associations between CA susceptibility and genetic variations in 3 members of the ADAMTS family. The largest risk for CA (OR 1.32, p = 0.006) was observed in carriers of the ADAMTS2 variant rs11750568, which has been previously associated with pediatric stroke. Three SNPs under investigation are associated with a protective effect in CA pathogenesis (ADAMTS12 variant rs1364044: OR 0.65, p = 0.0001; and ADAMTS13 variants rs739469 and rs4962153: OR 0.77 and 0.63, p = 0.02 and 0.0006, respectively), while 2 other ADAMTS13 variants may confer a significant risk (rs2301612: OR 1.26, p = 0.011; rs2285489: OR 1.24, p = 0.02). CONCLUSIONS These results suggest that reduced integrity of the endothelial wall, as conferred by ADAMTS variants, together with inflammatory processes and defective vascular remodeling plays an important role in CA pathogenesis, although the mechanism of action remains unknown. The authors' findings may lead to specific screening of at-risk populations in the future.
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Santamaria, Salvatore, and Rens de Groot. "ADAMTS proteases in cardiovascular physiology and disease." Open Biology 10, no. 12 (2020): 200333. http://dx.doi.org/10.1098/rsob.200333.
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The a disintegrin-like and metalloproteinase with thrombospondin motif (ADAMTS) family comprises 19 proteases that regulate the structure and function of extracellular proteins in the extracellular matrix and blood. The best characterized cardiovascular role is that of ADAMTS-13 in blood. Moderately low ADAMTS-13 levels increase the risk of ischeamic stroke and very low levels (less than 10%) can cause thrombotic thrombocytopenic purpura (TTP). Recombinant ADAMTS-13 is currently in clinical trials for treatment of TTP. Recently, new cardiovascular roles for ADAMTS proteases have been discovered. Several ADAMTS family members are important in the development of blood vessels and the heart, especially the valves. A number of studies have also investigated the potential role of ADAMTS-1, -4 and -5 in cardiovascular disease. They cleave proteoglycans such as versican, which represent major structural components of the arteries. ADAMTS-7 and -8 are attracting considerable interest owing to their implication in atherosclerosis and pulmonary arterial hypertension, respectively. Mutations in the ADAMTS19 gene cause progressive heart valve disease and missense variants in ADAMTS6 are associated with cardiac conduction. In this review, we discuss in detail the evidence for these and other cardiovascular roles of ADAMTS family members, their proteolytic substrates and the potential molecular mechanisms involved.
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Rodansky, Eva S., Justin K. Smith, Hugh J. L. Fryer, Robert S. Greenfield, and George M. Rodgers. "Inhibition of Endothelial Cell Tube Formation by ADAMTS13 Occurs Via Interaction with VEGF." Blood 116, no. 21 (2010): 4307. http://dx.doi.org/10.1182/blood.v116.21.4307.4307.
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Abstract Abstract 4307 The von Willebrand factor-cleaving protease, also known as ADAMTS13, is synthesized, in part, by endothelial cells (EC). We previously reported that proliferating EC secreted ∼3-fold more ADAMTS13 (antigen and activity) than confluent EC, and that this synthesis was transcriptionally regulated (SJ Kling et al, Pathophysiol Haemost Thromb 2008; 36: 233.) Thrombospondin domains, a defining feature of the ADAMTS protease family, in other ADAMTS family members mediate inhibition of angiogenesis. In particular, ADAMTS1 inhibits angiogenesis by sequestering vascular endothelial growth factor (VEGF) (A Luque et al, J Biol Chem, 2003; 278: 23656). Since ADAMTS13 also has thrombospondin domains, we hypothesized that ADAMTS13 might also mediate anti-angiogenic activity. Human umbilical vein EC angiogenesis was quantified by Angioquant analysis of fluorescence microscopy tube images in a Matrigel assay. Treatment of EC with inhibitors of angiogenesis (anti-VEGF, vasostatin) did not alter EC production of ADAMTS13. However, exogenous recombinant ADAMTS13 inhibited angiogenesis in a dose-dependent manner (Figure 1), in media containing VEGF. In VEGF-free media, ADAMTS13 had no effect on EC tube formation. Preincubation of ADAMTS13 with an antibody to the ADAMTS13 thrombospondin domains 5–7 partially reversed the inhibition of tube formation, implicating these domains in the anti-angiogenic interaction (Figure 2). We also found that VEGF co-immunoprecipitates with ADAMTS13, providing strong evidence that these two proteins interact. When EC lysates were crosslinked with DTSSP prior to immunoprecipitation, anti-ADAMTS13 immunoprecipitated as much VEGF as did anti-ADAMTS1, while an antibody to ADAM17, a similar protein that lacks thrombospondin domains, failed to co-immunoprecipitate VEGF (Figure 3). These data indicate that as with other ADAMTS family members, ADAMTS13 inhibits tubule formation - a parameter of angiogenesis – through its interaction with VEGF, an effect likely mediated by its thrombospondin domains. Inhibition of angiogenesis adds to the expanding roles of ADAMTS13 in down-regulation of thrombosis and inflammation. Fig. 1. Fig. 1. Fig. 2. Fig. 2. Fig. 3. An antibody to ADAMTS13 immunoprecipitates VEGF in similar amounts as anti-ADAMTS1 when proteins from HUVEC lysates are crosslinked prior to co-immunoprecipitation. Nonspecific IgG fails to immunoprecipitate VEGF, as does anti-ADAM17. (A1 = ADAMTS1; A13 = ADAMTS13) Fig. 3. An antibody to ADAMTS13 immunoprecipitates VEGF in similar amounts as anti-ADAMTS1 when proteins from HUVEC lysates are crosslinked prior to co-immunoprecipitation. Nonspecific IgG fails to immunoprecipitate VEGF, as does anti-ADAM17. (A1 = ADAMTS1; A13 = ADAMTS13) Disclosures: Fryer: American Diagnostica Inc: Employment. Greenfield:American Diagnostica Inc: Employment.
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Korchagina, Anastasia, and Pavel Krylov. "Philogenetic Analysis of ADAMTS-4 and ADAMTS-5 Structures." Natural Systems and Resources, no. 1 (July 2020): 5–11. http://dx.doi.org/10.15688/nsr.jvolsu.2020.1.1.
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ADAMTS-4 and -5 are aggrecanases that are involved in the development of osteoarthrosis by breaking aggrecan at various binding sites, of which cleavage in the Glu373-Ala374 bond plays the most important role in pathogenesis. Therefore, studying them is an urgent task to this day. Now, the structural features of these enzymes have already been studied, however, the influence of evolutionary development on their functions and enzymatic activity is not quite clear. In the framework of this research in silico studies have been conducted. They consist in the construction of phylogenetic trees by the maximum likelihood method in MEGA X program, the establishment of changes in the structures that occurred during evolution, and their possible effect on enzymatic activity. In addition, the organism most suitable for experimental studies has been determined. In this research, to analyze evolutionary changes, we have studied the sequences of organisms from different families: Salmon, Guinea fowl, Frog, Python, Rabbit, Leopard, Gorilla, Man. The lengths of these sequences are approximately equal; when aligning, the structures do not differ much. When studying the trees constructed from these sequences, it has been found that their structure is quite different only at the beginning, in the area of the signal surface and prodomain, while the rest of the changes are insignificant. The authors have also carried out the analysis of phylogenetic trees to determine an organism that is most like the human structure and therefore most suitable for in vivo studies. The following structures have been investigated: Bull, Camel, Pig, Donkey, Rabbit, Rat, Mouse, and Man. The rabbit has the most similar structure and therefore is more suitable for experimental studies.
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Verma, Priyanka, and Krishna Dalal. "ADAMTS-4 and ADAMTS-5: Key enzymes in osteoarthritis." Journal of Cellular Biochemistry 112, no. 12 (2011): 3507–14. http://dx.doi.org/10.1002/jcb.23298.
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Kenagy, Richard D., Seung-Kee Min, Alexander W. Clowes, and John D. Sandy. "Cell Death–associated ADAMTS4 and Versican Degradation in Vascular Tissue." Journal of Histochemistry & Cytochemistry 57, no. 9 (2009): 889–97. http://dx.doi.org/10.1369/jhc.2009.953901.
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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 ∼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.
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TURNER, SHARON L., DAVID MANGNALL, NIGEL C. BIRD, ROWENA A. D. BUNNING, and MARIA E. BLAIR-ZAJDEL. "Expression of ADAMTS-1, ADAMTS-4, ADAMTS-5 and TIMP3 by hepatocellular carcinoma cell lines." International Journal of Oncology 41, no. 3 (2012): 1043–49. http://dx.doi.org/10.3892/ijo.2012.1525.
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Troeberg, Linda, Barbara Mulloy, Peter Ghosh, Meng-Huee Lee, Gillian Murphy, and Hideaki Nagase. "Pentosan polysulfate increases affinity between ADAMTS-5 and TIMP-3 through formation of an electrostatically driven trimolecular complex." Biochemical Journal 443, no. 1 (2012): 307–15. http://dx.doi.org/10.1042/bj20112159.
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The semi-synthetic sulfated polysaccharide PPS (pentosan polysulfate) increases affinity between the aggrecan-degrading ADAMTSs (adamalysins with thrombospondin motifs) and their endogenous inhibitor, TIMP (tissue inhibitor of metalloproteinases)-3. In the present study we demonstrate that PPS mediates the formation of a high-affinity trimolecular complex with ADAMTS-5 and TIMP-3. A TIMP-3 mutant that lacks extracellular-matrix-binding ability was insensitive to this affinity increase, and truncated forms of ADAMTS-5 that lack the Sp (spacer) domain had reduced PPS-binding ability and sensitivity to the affinity increase. PPS molecules composed of 11 or more saccharide units were 100-fold more effective than those of eight saccharide units, indicating the involvement of extended or multiple protein-interaction sites. The formation of a high-affinity trimolecular complex was completely abolished in the presence of 0.4 M NaCl. These results suggest that PPS enhances the affinity between ADAMTS-5 and TIMP-3 by forming electrostatically driven trimolecular complexes under physiological conditions.
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Tajima, Takuya, Nami Yamaguchi, Takuji Yokoe, Etsuo Chosa, and Yudai Morita. "A possible issue of articular cartilage degeneration in acute phase after anterior cruciate ligament reconstruction." Orthopaedic Journal of Sports Medicine 9, no. 7_suppl4 (2021): 2325967121S0021. http://dx.doi.org/10.1177/2325967121s00218.
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Objectives: Intra-articular hematoma are caused by articular injury such as ligament rupture or intra-articular fracture and following knee surgery. It has been reported that intra-articular hematoma leads to cartilage degeneration. Exposure of articular cartilage to low concentrations of blood for a period as short as 2 days has been confirmed to induce the irreversible cartilage damage. Anterior cruciate ligament (ACL) injury is increased risk for developing posttraumatic osteoarthritis (OA). Despite improvement in ACL reconstruction (ACLR), the incidence of posttraumatic OA has remained relatively unchanged over the several decades later. One of cause in OA may be thought to intra-articular hematoma after ACLR. A primary feature in OA is cartilage degeneration, it involves the loss of extracellular matrix components including aggrecan and Type Ⅱ collagen. A distintegrin and metalloprotease with thrombospondin motifs (ADAMTS)-4, -5, -9 and matrix metalloprotease (MMP)-2, -9 are reported primary proteases responsible for aggrecan cleavage in OA. The present study was designed to the hypothesis described as above by evaluating the influence of intra-articular hematoma on ADAMTS-4, -5, -9, MMP-2 and -9 activities in acute phase after ACLR. Methods: Patient sample Intra-articular hematoma was collected from patients, who were underwent primary ACLR with consent to participate in this study, on day1, 4 and 7 after surgery. Day1 samples were collected from drainage tube for approximately 10 ml. Day4 and day7 samples were collected by inserted needle and aspiration under sterile condition. For control sample, it was selected and adopted SF without intra-articular hematoma. To obtain enough amount of SF for control sample on the ipsilateral knee, 20ml of 0.9% saline was injected into the joint cavity prior to arthroscopic surgery. In the laboratory, intra-articular hematoma and SF were centrifuged for 15 min at 3000g and the supernatant were stored at -80℃ until assay. From March 2017 to March 2020, 98 patients who were undergone knee arthroscopic surgery took part in this study. The study protocol was reviewed and approved (accession no.: O-0149) by the local ethics committees at our institutions. The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Written informed consent was obtained from the patients for publication of this report. The patients who did not want to take part were not enrolled in this study. Inclusion criteria include patients for primary ACLR in our institute. Exclusion criteria include osteoarthritis with Kellgren-Lawrence classification gradeⅡ or higher on X-ray, cartilage damage with International Cartilage Repair Society (ICRS) cartilage injury classification gradeⅡ or higher based on arthroscopic findings and multi-ligament reconstruction. Enzyme-linked Immunosorbent assay (ELISA) Five proteins (ADAMTS-4, -5, -9 and MMP-2, -9) were analyzed and were measured in intra-articular hematoma and SF using a human ELISA kit (Cloud-Clone Corp, Katy, TX, USA according to manufacturer’s instructions. ADAMTS and MMPs (catalog number): (ADAMTS4, SEK204Hu; ADAMTS5, SEK205Hu; ADAMTS9, SEK209Hu; MMP2, SEA100Hu; MMP9, SEA553Hu) levels of intra-articular hematoma and SF were read off from a standard curve according to the manufacturer’s instruction. Results: Expression levels of each proteins in intra-articular hematoma using ELISA The expression levels of ADAMTS-4 in day4 and day7 samples were significantly higher than in control and day1 samples.(Pc-4<0.001, Pc-7<0.001, P1-4<0.001, P1-7<0.001). The expression levels of ADAMTS-4 in day7 samples also were significantly higher than in day4 samples (P4-7<0.05). Those of ADAMTS-5 in day1, day4 and day7 samples were significantly higher than in control samples.(Pc-1<0.001, Pc-4<0.001, P1-7<0.001). The expression levels of ADAMTS-9 were no significantly differences between each samples. MMP-2 expression levels of day1 and day4 samples were significantly increased compared with the control samples (P c-1<0.05, P c-4<0.05). The expression levels of MMP-9 were increased only day1 samples, significantly higher than in control, day4 and day7 samples(Pc-1<0.001, P1-4<0.001, P1-7<0.001). ELISA analysis of control and post-operative samples : Time-course study In day1 after surgery, expression levels of ADAMTS-5, MMP-2 and MMP-9 were increased significantly compared with those of control samples (ADAMTS-5: P c-1<0.001, MMP-2: P c-1<0.05, MMP-9: P c-1<0.001). In day4, expression of ADAMTS-5 and MMP-2 were increased significantly higher than control samples (respectively, P c-4<0.001). MMP-9 levels of day4 were decreased significantly compared with day1 samples (P 1-4<0.001). In day7, expression of ADAMTS-5 were increased significantly higher than control samples (P c-7<0.001). Expression levels of MMP-2 and MMP-9 in day7 were no significantly differences compared with control samples. Those of MMP-9 were decreased significantly lower than day1 samples (P 1-7<0.001). On the other hand, ADAMTS-4 expression levels revealed significantly increased expression at day4 (P<0.001) and day7 (P<0.001). ADAMTS-4 expression levels were shown to increase in time-course dependency. Conclusions: Because the expression of ADAMTS-4, -5 and MMP-2, -9 were elevated in acute phase after ACLR, that suggested that intra-articular hematoma after ACLR may contribute to cartilage degeneration. The results suggest that immediate treatment for intra-articular hematoma, such as injection and aspiration, may be needed for prevention of OA. Moreover, these proteins may provide potential for therapeutic targets.
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Wang, Zhengke, Junming Luo, Satori Iwamoto, and Qian Chen. "Matrilin-2 Is Proteolytically Cleaved by ADAMTS-4 and ADAMTS-5." Molecules 19, no. 6 (2014): 8472–87. http://dx.doi.org/10.3390/molecules19068472.
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Scully, Marie, Richard Starke, Richard Lee, Ian Mackie, Samuel J. Machin, and Hannah Cohen. "Successful Pregnancy Outcome in 5 Patients with Thrombotic Thrombocytopenic Purpura." Blood 106, no. 11 (2005): 3016. http://dx.doi.org/10.1182/blood.v106.11.3016.3016.
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Abstract Pregnancy is an initiating event for acute thrombotic thrombocytopenic purpura (TTP). Patients with a history of TTP have a high risk of relapse during pregnancy with associated maternal and fetal morbidity/mortality. We report 5 TTP patients who underwent serial clinical and laboratory monitoring (haemoglobin, platelets, blood film, reticulocytes, lactate dehydrogenase (LDH), ADAMTS-13 activity and IgG antibodies) and treatment within a specialist obstetric/haematology clinic, resulting in successful pregnancy outcomes. Patients: Cases 1 and 2 presented with TTP in their first pregnancy and had second trimester fetal losses. Case 3 had four TTP relapses and soon after achievement of clinical remission became pregnant. Case 4 had a single acute episode of TTP 6 years prior to pregnancy and normal ADAMTS 13 activity at the onset of pregnancy. Case 5 presented with acute TTP and a left sided stroke at 16 weeks gestation. ADAMTS-13 activity was <5% at onset of pregnancy in cases 1–3 and at presentation of TTP during pregnancy in case 5. Only case 3 had IgG antibodies to ADAMTS13. Cases 1–3 received regular plasma exchange (PEX) every 2 weeks initially, starting during the first trimester, with ADAMTS 13 activity levels maintained >15% during pregnancy (range 15–78%, normal range 66–126%) by collagen binding assay. Case 4 had normal laboratory parameters, including serial ADAMTS 13 activity levels, throughout pregnancy, requiring no specific therapy for TTP. Case 5 received intensive PEX (84 procedures) and pulsed methylprednisolone during pregnancy. Rituximab (375mg/m2, weekly for 4 weeks) was given at 28 weeks gestation with no observed toxicity except asymptomatic transient neonatal neutropenia. All 5 cases continued low dose aspirin (75 mg daily) throughout pregnancy. Case 1 and 2 received prophylactic low molecular weight heparin (LMWH) and cases 3 and 5 received treatment doses of LMWH for pulmunory emboli and TTP associated stroke at presentation. Live healthy infants were delivered in all 5 cases in the third trimester (31–41 weeks). These data suggest successful pregnancy outcome is achievable in patients with a history of TTP/acute TTP with therapy based on close clinical and laboratory monitoring. Regular PEX in patients with a history of TTP and severely reduced ADAMTS 13 activity/IgG antibodies to ADAMTS 13 at the onset of pregnancy was associated with successful pregnancy outcome. Serial ADAMTS 13 activity and antibody levels during pregnancy and post-partum provided a useful adjunct to decision making on intensity of treatment.
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Dancevic, Carolyn M., Daniel R. McCulloch, and Alister C. Ward. "The ADAMTS hyalectanase family: biological insights from diverse species." Biochemical Journal 473, no. 14 (2016): 2011–22. http://dx.doi.org/10.1042/bcj20160148.
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The a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs (ADAMTS) family of metzincins are complex secreted proteins that have diverse functions during development. The hyalectanases (ADAMTS1, 4, 5, 8, 9, 15 and 20) are a subset of this family that have enzymatic activity against hyalectan proteoglycans, the processing of which has important implications during development. This review explores the evolution, expression and developmental functions of the ADAMTS family, focusing on the ADAMTS hyalectanases and their substrates in diverse species. This review gives an overview of how the family and their substrates evolved from non-vertebrates to mammals, the expression of the hyalectanases and substrates in different species and their functions during development, and how these functions are conserved across species.
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Rogerson, Fraser, Karena Last, Suzanne Golub, et al. "ADAMTS-9 in Mouse Cartilage Has Aggrecanase Activity That Is Distinct from ADAMTS-4 and ADAMTS-5." International Journal of Molecular Sciences 20, no. 3 (2019): 573. http://dx.doi.org/10.3390/ijms20030573.
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A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 and ADAMTS-5 are the principal aggrecanases in mice and humans; however, mice lacking the catalytic domain of both enzymes (TS-4/5∆cat) have no skeletal phenotype, suggesting there is an alternative aggrecanase for modulating normal growth and development in these mice. We previously identified aggrecanase activity that (a) cleaved at E↓G rather than E↓A bonds in the aggrecan core protein, and (b) was upregulated by retinoic acid but not IL-1α. The present study aimed to identify the alternative aggrecanase. Femoral head cartilage explants from TS-4/5∆cat mice were stimulated with IL-1α or retinoic acid and total RNA was analysed by microarray. In addition to ADAMTS-5 and matrix metalloproteinase (MMP)-13, which are not candidates for the novel aggrecanase, the microarray analyses identified MMP-11, calpain-5 and ADAMTS-9 as candidate aggrecanases upregulated by retinoic acid. When calpain-5 and MMP-11 failed to meet subsequent criteria, ADAMTS-9 emerged as the most likely candidate for the novel aggrecanase. Immunohistochemistry revealed ADAMTS-9 expression throughout the mouse growth plate and strong expression, particularly in the proliferative zone of the TS-4/5-∆cat mice. In conclusion, ADAMTS-9 has a novel specificity for aggrecan, cleaving primarily at E↓G rather than E↓A bonds in mouse cartilage. ADAMTS-9 might have more important roles in normal skeletal development compared with ADAMTS-4 and ADAMTS-5, which have key roles in joint pathology.
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Korchagina, Anastasia, and Lyudmila Derevshchikova. "Structural and Functional Characteristics of ADAMTS-4 and ADAMTS-5: A Review." Natural Systems and Resources, no. 1 (July 2020): 12–21. http://dx.doi.org/10.15688/nsr.jvolsu.2020.1.2.
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ADAMTS-4 and -5 are aggrecanases that are involved in the development of osteoarthrosis, one of the most common diseases at the moment, due to which a large number of people suffer annually. By some estimates, 9.6% of men and 18% of women over the age of 60 have symptomatic osteoarthrosis. This review discusses the currently known data on the structural features and enzymatic activity of these enzymes. The structures of ADAMTS-4 and -5 are similar, they contain 7 domain sites: the signal section, the N-terminal prodomain, the catalytic domain, the disintegrin-like domain, the thrombospodin motif, the cysteine-rich domain, and the spacer domain. In addition to all these elements, ADAMTS-5 has an additional thrombospodin motif at the end. ADAMTS-4 and -5 cleaves aggrecan in 5 different binding sites. However, the Glu373-Ala374 site probably plays the most important role in the pathogenesis, since when this bond is broken, the whole aggrecan molecule loses its integrity, which leads to the destruction of cartilage and the development of the disease. In the course of the analysis of the information, the authors have found that the participation of ADAMTS-4 and -5 in the development of osteoarthritis varies greatly depending on the type of organism. The researchers have established that in mice ADAMTS-4 plays the largest role in the destruction of aggrecan, while in humans ADAMTS-5 or both aggrecanases influence the development of osteoarthritis. The revealed differences are not fully described; therefore, this review summarizes the already known results in this area, which will facilitate further research in this direction.
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Rees, Alison J., Chris B. Little, Bruce Caterson, and Clare E. Hughes. "ADAMTS-4 and ADAMTS-5 sequestration and activity in chondrocyte-agarose cultures." International Journal of Experimental Pathology 85, no. 1 (2008): A23—A24. http://dx.doi.org/10.1111/j.0959-9673.2004.369ad.x.
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Moncada-Pazos, Angela, Alvaro J. Obaya, Cristina G. Viloria, Carlos López-Otín, and Santiago Cal. "The nutraceutical flavonoid luteolin inhibits ADAMTS-4 and ADAMTS-5 aggrecanase activities." Journal of Molecular Medicine 89, no. 6 (2011): 611–19. http://dx.doi.org/10.1007/s00109-011-0741-7.
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Tayman, Mahmure A., İsmail Koyuncu, and Nimet Ö. Köklü. "Expression Levels of A Disintegrin-like Metalloproteinase with Thrombospondin Motifs-4 and -5 (ADAMTS-4 and ADAMTS-5) in Inflamed and Healthy Gingival Tissues." Combinatorial Chemistry & High Throughput Screening 23, no. 2 (2020): 168–76. http://dx.doi.org/10.2174/1386207323666200218113000.
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Background: ADAMTS (A disintegrin-like metalloproteinase with thrombospondin motifs) is a group of 19 zinc-dependent metalloproteases known to function in many pathological and physiological processes, such as adhesion, cell fusion, signaling, proteolysis and ECM degradation. Objectives: The aim of this study was to demonstrate the levels of ADAMTS-4 and -5 in gingival tissues with Stage III-Grade B generalized periodontitis (SIII-GB), Stage III-Grade C generalized periodontitis (SIII-GC) and healthy-control (C) groups. Methods: The clinical measurements were recorded for each patient. A total of 63 gingival biopsy specimens were obtained from the C (n:20), SIII-GB (n:23) and SIII-GC (n:20) groups. Polymerase chain reaction (Rt-PCR) and immunohistochemical (IHC) examinations were used to determine gene and protein levels. Results: According to the results of all methods, ADAMTS-4 and -5 expressions existed in periodontitis and C groups (P> 0.05). Immunostaining for ADAMTS-4 was found to be higher in patients with periodontitis than for ADAMTS-5 (P>0.05). Gene expression levels for ADAMTS-4 and -5 seemed to be up-regulated in subjects diagnosed with periodontitis, but the results were not statistically significant (P>0.05). A positive correlation was observed between PPD and ADAMTS-4 mRNA in SIII-GC (p=0.035) and SIII-GB (p=0.015). A positive correlation was determined between ADAMTS-4 mRNA and ADAMTS-5 mRNA in SIII-GC (p=0.037) and SIII-GB (p=0.00). Conclusion: ADAMTS expression may take part in both pathological and physiological processes in the periodontal tissues, and periodontal destruction may be the result of a complex interaction of several pathways with many participants, such as ADAMTS-4 and -5, thus facilitating the exaggeration of periodontal disease.
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Fosang, AJ, FM Rogerson, CJ East, and H. Stanton. "ADAMTS-5: The story so far." European Cells and Materials 15 (February 5, 2008): 11–26. http://dx.doi.org/10.22203/ecm.v015a02.
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Gendron, Christi, Masahide Kashiwagi, Ngee Han Lim, et al. "Proteolytic activities of human ADAMTS-5." Journal of Biological Chemistry 282, no. 38 (2007): 28296. http://dx.doi.org/10.1016/s0021-9258(20)58727-9.
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Gendron, Christi, Masahide Kashiwagi, Ngee Han Lim, et al. "Proteolytic Activities of Human ADAMTS-5." Journal of Biological Chemistry 282, no. 25 (2007): 18294–306. http://dx.doi.org/10.1074/jbc.m701523200.
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Wang, Zhen, Di Ye, Jing Ye, et al. "ADAMTS-5 Decreases in Coronary Arteries and Plasma from Patients with Coronary Artery Disease." Disease Markers 2019 (December 18, 2019): 1–9. http://dx.doi.org/10.1155/2019/6129748.
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The current study demonstrates that a disintegrin and metalloproteinase with thrombospondin type 1 motif- (ADAMTS-) 5 is a key extracellular matrix protease and associated with cardiovascular diseases. However, the plasma ADAMTS-5 levels and relevance of coronary artery disease (CAD) remain largely unknown. This study is aimed at examining the relationship between the plasma ADAMTS-5 levels and the severity of coronary stenosis in patients with CAD. In the present study, the expression of ADAMTS-5 was analyzed in coronary artery samples and blood. The results showed that the plasma ADAMTS-5 levels were lower in the CAD group than in the control group. In addition, significantly higher matrix metalloproteinase- (MMP-) 2 and MMP-9 levels were also observed in the patients with CAD, and the ADAMTS-5 levels were negatively correlated with the MMP-2 and MMP-9 levels. Spearman’s correlation analysis showed that the Gensini score was negatively correlated with the ADAMTS-5 levels but was positively correlated with the MMP-2 and MMP-9 levels. Receiver-operating characteristic (ROC) analysis revealed that ADAMTS-5, MMP-2, and MMP-9 may have a certain diagnostic value in CAD and that the combination of all three metalloproteinases had a higher diagnostic value. The findings provided a better understanding of the role of ADAMTS-5 in the diagnosis of CAD.
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Addinsall, Alex, Leonard Forgan, Natasha McRae, et al. "Treatment of Dystrophic mdx Mice with an ADAMTS-5 Specific Monoclonal Antibody Increases the Ex Vivo Strength of Isolated Fast Twitch Hindlimb Muscles." Biomolecules 10, no. 3 (2020): 416. http://dx.doi.org/10.3390/biom10030416.
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Aberrant extracellular matrix synthesis and remodeling contributes to muscle degeneration and weakness in Duchenne muscular dystrophy (DMD). ADAMTS-5, a secreted metalloproteinase with catalytic activity against versican, is implicated in myogenesis and inflammation. Here, using the mdx mouse model of DMD, we report increased ADAMTS-5 expression in dystrophic hindlimb muscles, localized to regions of regeneration and inflammation. To investigate the pathophysiological significance of this, 4-week-old mdx mice were treated with an ADAMTS-5 monoclonal antibody (mAb) or IgG2c (IgG) isotype control for 3 weeks. ADAMTS-5 mAb treatment did not reduce versican processing, as protein levels of the cleaved versikine fragment did not differ between hindlimb muscles from ADAMTS-5 mAb or IgG treated mdx mice. Nonetheless, ADAMTS-5 blockade improved ex vivo strength of isolated fast extensor digitorum longus, but not slow soleus, muscles. The underpinning mechanism may include modulation of regenerative myogenesis, as ADAMTS-5 blockade reduced the number of recently repaired desmin positive myofibers without affecting the number of desmin positive muscle progenitor cells. Treatment with the ADAMTS-5 mAb did not significantly affect markers of muscle damage, inflammation, nor fiber size. Altogether, the positive effects of ADAMTS-5 blockade in dystrophic muscles are fiber-type-specific and independent of versican processing.
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Mao, Guping, Peihui Wu, Ziji Zhang та ін. "MicroRNA-92a-3p Regulates Aggrecanase-1 and Aggrecanase-2 Expression in Chondrogenesis and IL-1β-Induced Catabolism in Human Articular Chondrocytes". Cellular Physiology and Biochemistry 44, № 1 (2017): 38–52. http://dx.doi.org/10.1159/000484579.
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Background/Aims: Aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5) are secreted enzymes belonging to the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family that play significant roles in the progression of osteoarthritis (OA). Here, we aimed to determine whether the expression of ADAMTS-4/5 in chondrogenesis and inflammation is regulated by microRNA-92a-3p (miR-92a-3p). Methods: MiR-92a-3p and ADAMTS-4/5 expressions were determined by quantitative polymerase chain reaction (qPCR). To investigate the repressive effect of miR-92a-3p on ADAMTS-4/5 expression, chondrogenic human mesenchymal stem cells (hMSCs) and human chondrocytes were transfected with mature miR-92a-3p or an antisense inhibitor (anti-miR-92a-3p), respectively. ADAMTS-4/5 protein production was quantified by enzyme-linked immunosorbent assay (ELISA), and miR-92a-3p involvement in IL-1β-mediated catabolic effects was examined by immunoblotting. The roles of activated MAP kinases (MAPK) and nuclear factor (NF)-κB were evaluated by using specific inhibitors. Interaction between miR-92a-3p and its putative binding site in the 3′-untranslated region (3′-UTR) of ADAMTS-4/5 mRNA was confirmed by luciferase reporter assay. Results: miR-92a-3p expression was elevated in chondrogenic hMSCs, with significantly lower expression in OA cartilage than in normal cartilage. Stimulation with IL-1β significantly reduced miR-92a-3p expression in primary human chondrocytes (PHCs). Transfection of chondrocytes with miR-92a-3p downregulated IL-1β-induced ADAMTS-4/5 expression, and the activity of a reporter construct containing the 3′-UTR of human ADAMTS-4/5 mRNA. MiR-92a-3p expression was suppressed upon IL-1β-induced activation of MAPK and NF-κB in chondrocytes. Conclusion: MiR-92a-3p is an important regulator of ADAMTS-4/5 in human chondrocytes and may contribute to the development of OA.
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García-Faroldi, Gianni, Elin Rönnberg, Adolfo Orro, et al. "ADAMTS: Novel proteases expressed by activated mast cells." Biological Chemistry 394, no. 2 (2013): 291–305. http://dx.doi.org/10.1515/hsz-2012-0270.
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Abstract Here we show that mast cells (MCs) express the metalloproteases of the A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family, and that ADAMTS expression is influenced by MC activation. Co-culture of MCs with live Gram-positive bacteria caused a profound induction of ADAMTS-9 and -6, as well as down-regulated expression of ADAMTS-5. Similar patterns were also seen after MC activation with calcium ionophore and by immunoglobulin E receptor crosslinking. Moreover, ADAMTS-5, -6 and -9 were all induced by activation of terminally differentiated murine peritoneal MCs and in a human MC line. ADAMTS-9 up-regulation in response to immunoglobulin E receptor crosslinking was strongly dependent on Gö6976-sensitive protein kinase C and partly dependent on nuclear factor of activated T cells and nuclear factor kappa-light-chain-enhancer of activated B cells, respectively. The expression of ADAMTS-5, -6 and -9 was closely linked to MC maturation, as shown by their strong induction during the differentiation of bone marrow precursor cells into mature MCs. ADAMTS family members have been shown to possess aggrecanase activity. Accordingly, MCs were shown to express aggrecanase activity. Finally, ADAMTS-5 protein was detected in MCs by immunocytochemistry. Taken together, the present study reveals ADAMTS expression by MCs and that MC activation regulates the expression of these proteases, thus implicating the ADAMTS family of proteases in MC function.
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Lee, So-Young, Hyang-Sin Lee, Minchan Gil, et al. "Differential Expression Patterns of a Disintegrin and Metalloproteinase With Thrombospondin Motifs (ADAMTS) -1, -4, -5, and -14 in Human Placenta and Gestational Trophoblastic Diseases." Archives of Pathology & Laboratory Medicine 138, no. 5 (2014): 643–50. http://dx.doi.org/10.5858/arpa.2012-0227-oa.
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Context.—The ability of intermediate trophoblasts to invade maternal tissue during placentation depends on how well they can degrade the extracellular matrix. Invasion into the extracellular matrix requires many complex proteases. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) is a novel family of secreted metalloproteinases. The ADAMTS-1, -4, -5, and -14 subtypes are known to be expressed in human placenta, but little is understood about their expression patterns. Objective.—To examine the expression patterns of ADAMTS-1, -4, -5, and -14 in specific human placenta cell types during gestation and in gestational trophoblastic diseases. Design.—Placental tissues were obtained from 25 pregnant women and 21 cases of gestational trophoblastic diseases (10 early complete moles, 3 placental site trophoblastic tumors, 4 invasive moles, and 4 choriocarcinomas). The expression of the 4 ADAMTS was analyzed by immunohistochemistry. Results.—ADAMTS-1, -4, -5, and -14 were differentially expressed by the human placenta throughout gestation in a time-specific and cell type–specific manner, as well as in gestational trophoblastic diseases. ADAMTS-1 showed gradually strong staining intensity in gestational trophoblastic diseases according to the invasive potential but showed consistent strong intensity throughout normal placenta. ADAMTS-4 and ADAMTS-5 exhibited higher and restricted expression in first-trimester intermediate trophoblasts. They also exhibited comparably strong expression in gestational trophoblastic diseases. However, ADAMTS-14 expression remained unchanged throughout gestation. Conclusions.—The restricted expression pattern of ADAMTS-4 and ADAMTS-5 and their increased expression in gestational trophoblastic diseases suggest that these 2 ADAMTS subtypes are associated with a biological phenotype of trophoblasts involved in human placentation and the development of gestational trophoblastic diseases.
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Chen, Ling, Jun Tang, Yixiao Feng, et al. "ADAMTS9 is Silenced by Epigenetic Disruption in Colorectal Cancer and Inhibits Cell Growth and Metastasis by Regulating Akt/p53 Signaling." Cellular Physiology and Biochemistry 44, no. 4 (2017): 1370–80. http://dx.doi.org/10.1159/000485534.
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Background/Aims: ADAMTS (disintegrin-like and metalloproteinase with thrombospondin motifs) proteins are extracellular zinc metalloproteinases that play an important role in extracellular matrix assembly and degradation, connective tissue structuring, angiogenesis, and cell migration. Multiple studies suggest that ADAMTS proteins (e.g. ADAMTS9) can act as tumor suppressors. In gastric, esophageal, and nasopharyngeal carcinomas ADAMTS9 is frequently down-regulated by promoter methylation. Whether ADAMTS9 can function as a tumor suppressor gene (TSG) in colorectal cancer is still unclear. Methods: We performed immunohistochemistry, RT-PCR, and qRT-PCR, to examine the expression of ADAMTS9 in colorectal cancer cell lines and primary colorectal cancer tissues. Methylation-specific PCR was also carried out to investigate the promoter methylation status of ADAMTS9. We also explored the functions of ADAMTS9 in colorectal cancer cell lines through in vitro experiments. Results: ADAMTS9 expression was down-requlated or silenced in 83.3% (5/6) of colorectal cancer cell lines, and frequently repressed in 65.6% (21/32) of colorectal cancer tissues. Down-regulation of ADAMTS9 was partially due to promoter methylation. Exogenous expression of ADAMTS9 in colorectal cancer cell lines inhibited cell proliferation and migration through the regulation of cell cycle and apoptosis. In addition, ADAMTS9 prevented the activation of Akt, and its downstream targets in colorectal cancer cell lines. Conclusion: Our findings suggest ADAMTS9 is a TSG in colorectal cancer.
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Haddock, G., A. K. Cross, J. Plumb, et al. "Expression of ADAMTS-1, -4, -5 and TIMP-3 in normal and multiple sclerosis CNS white matter." Multiple Sclerosis Journal 12, no. 4 (2006): 386–96. http://dx.doi.org/10.1191/135248506ms1300oa.
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ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) -1, -4 and -5 proteases have been identified in the CNS at the mRNA level. These glutamyl endopeptidases, inhibited by tissue inhibitor of metalloproteinases (TIMP)-3, are key enzymes in the degradation of the aggregating chondroitin sulphate proteoglycans (CSPGs), and may therefore play a role in CNS extracellular matrix (ECM) changes in multiple sclerosis (MS). We have investigated ADAMTS and TIMP-3 expression in normal and MS CNS white matter by real-time RT-PCR, western blotting and immunohistochemistry. We report for the first time the presence of ADAMTS-1, -4 and -5 in normal and MS white matter. Levels of ADAMTS-1 and -5 mRNA were decreased in MS compared to normal tissue, with no significant change in ADAMTS-4 mRNA levels. Protein levels of ADAMTS-4 were significantly higher in MS tissue compared to normal tissue. Immunohistochemical studies demonstrated that ADAMTS-4 was associated predominantly with astrocytes with increased expression within MS lesions. TIMP-3 mRNA was significantly decreased in MS compared to controls. These studies suggest a role for ADAMTS-4 in the pathogenesis of MS. Further studies on the activity of ADAMTS-4 will enable a better understanding of its role in the turnover of the ECM of white matter in MS.
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Geiter, Sabine, Markus Graf, and Helga Vetr. "Correlation between Two ADAMTS-13 Activity Assays Based on Different Principles." Blood 110, no. 11 (2007): 3159. http://dx.doi.org/10.1182/blood.v110.11.3159.3159.
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Abstract Defects in ADAMTS-13, the von Willebrand Factor (vWF) cleaving protease, are thought to be the main cause for the microvascular thrombotic disorder TTP (thrombotic thrombocytopenic purpura) that is in more than 90% of cases fatal if not treated early and appropriately. Usually this disease is clinically diagnosed, but in recent years the need for rapid and reliable diagnostic tests for ADAMTS-13 levels has increased. We present here the comparison of two commercially available assays for quantification of ADAMTS-13 activity both suitable for routine analysis but based on different principles. The two assays differ in their test principle and the readout system as follows: Assay 1 is a fluorogenic assay using a FRETS-vWF73 substrate and a kinetic measurement (TECHNOZYM®ADAMTS-13 ELISA); with this assay ADAMTS13 Antigen can also be determined in a second step. Assay 2 is a chromogenic assay and detects the cleaved vWF73 substrate by a specific monoclonal antibody (TECHNOZYM®ADAMTS-13 Activity ELISA). Citrated plasma of normal donors (n=7), of pooled normal plasma (n=15) and of TTP patients (n=14) were tested in both assays. Results are reported in both assays as percentage of normal activity. The standard for both assays is prepared from a pool of 100 normal donors and defined as 100%. The samples comprised a range from 0.2% up to 107% activity. The overall correlation coefficient between the two different activity assays was 0.96. 5 samples were found to have less than 5% activity in both assays. These results show that data obtained by the new TECHNOZYM®ADAMTS-13 Activity ELISA correlate very well with the fluorogenic assay (TECHNOZYM®ADAMTS-13 ELISA) in spite of the fact that these assays are based on very different principles.
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Huang, K., and LD Wu. "Aggrecanase and Aggrecan Degradation in Osteoarthritis: A Review." Journal of International Medical Research 36, no. 6 (2008): 1149–60. http://dx.doi.org/10.1177/147323000803600601.
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Aggrecanase-mediated aggrecan degradation is a significant event in early-stage osteoarthritis (OA). Aggrecanases belonging to the ‘A Disintegrin And Metalloproteinase with ThromboSpondin motifs’ (ADAMTS) family of proteinases play a significant role in aggrecan depletion in osteoarthritic cartilage. There has been considerable interest in the possible role of these aggrecanases, especially ADAMTS-4 and ADAMTS-5, as therapeutic targets in OA. This article discusses recent data regarding ADAMTS-4 and ADAMTS-5 in OA, with emphasis on the relationship between aggrecanase and aggrecan degradation as well as the role of aggrecanase in OA.
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Santamaria, Salvatore. "ADAMTS‐5: A difficult teenager turning 20." International Journal of Experimental Pathology 101, no. 1-2 (2020): 4–20. http://dx.doi.org/10.1111/iep.12344.
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Peyvandi, Flora, Silvia Ferrari, Silvia Lavoretano, Maria T. Canciani, and Pier M. Mannucci. "A Multicentre Study on 100 Cases with Thrombotic Thrombocytopenic Purpura: The Role of Adamts-13 Activity and Anti-Adamts-13 Antibodies." Blood 104, no. 11 (2004): 2581. http://dx.doi.org/10.1182/blood.v104.11.2581.2581.
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Abstract Background: The metalloprotease ADAMTS-13 disposes physiologically of the unusually large molecular forms of the von Willebrand factor (VWF), that have the property to aggregate platelets in the microcirculation in the presence of high shear forces. The congenital or acquired deficiency of ADAMTS-13 has been specifically associated with a diagnosis of thrombotic thrombocytopenic purpura (TTP), a rare microangiopathy characterised by the massive formation of occlusive platelet thrombi in the microcirculation. Aim of the study: To investigate the pathogenic mechanism of TTP in 100 patients referred from 6 different countries and diagnosed on the basis of the presence of at least 3 of the followings laboratory abnormalities or clinical signs: thrombocytopenia, hemolytic anemia, elevated serum level of lactadehydrogenase and neurological symptoms compatible with focal ischemia. Materials and methods: ADAMTS-13 levels were measured in all patients’ plasma by Collagen Binding assay as previously described (Gerritsen et al., Thromb Haemost 1999); anti-ADAMTS-13 neutralizing antibodies was measured only in patients with low ADAMTS-13 levels, whereas candidate gene mutations were searched only in patients who had low ADAMTS-13 levels (less than 20%) not explained by detectable anti-ADAMTS-13 antibodies, whether or not there was a family history of TTP. Results: Plasma levels of ADAMTS-13 were severely reduced (&lt;10% of normal) in 48% of the cases, moderately reduced (between 10 and 46%) in 24% and normal (&gt;46%) in 28%. An antibody was identified as the cause of the deficiency in 38% the cases: the great majority of the patients with detectable inhibitor (87%) had severe ADAMTS-13 deficiency but 5 (13%) had moderately reduced ADAMTS-13 activity (ranging from 11 to 25%). Mutation analysis of the ADAMTS13 gene, carried on 15 patients, revealed a genetic variant in only two patients born from consanguineous marriages. The first case was a double heterozygosity for a 29 base pair deletion in exon 3 (291–319del) and a single nucleotide insertion in exon 29 (4143insA). The 290–319del and 4143insA mutations lead to premature stops at codons 368 and 1387 respectively. The second one consisted in a homozygosity for a 6 base pair deletion in exon 23 (2930–2935del). This deletion leads to a substitution of Cys 977 by Trp, and a deletion of 2 aminoacids, Ala and Arg, at residues 978 and 979 respectively. Conclusion: The study of this large series of patients with TTP indicates that in nearly one third of patients ADAMTS-13 levels were normal. In more than half of the patients with low plasma level of the protease, ADAMTS-13 deficiency was not due to the presence of inactivating antibodies or gene abnormalities. An unexpected observation was that an inhibitor was also found in 5 patients with moderately reduced levels of ADAMTS-13.
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Szeremeta, Anna, Agnieszka Jura-Półtorak, Aleksandra Zoń-Giebel, Magdalena Kopeć-Mędrek, Eugeniusz Józef Kucharz та Krystyna Olczyk. "Aggrecan Turnover in Women with Rheumatoid Arthritis Treated with TNF-α Inhibitors". Journal of Clinical Medicine 9, № 5 (2020): 1377. http://dx.doi.org/10.3390/jcm9051377.
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This study was performed to evaluate the effects of 15-month anti-tumor necrosis factor α (anti-TNF-α) therapy on the aggrecan turnover of female rheumatoid arthritis (RA) patients. Serum was obtained from healthy subjects and female RA patients treated with TNF-α inhibitors (TNFαI) in combination with methotrexate. We measured serum levels of aggrecan chondroitin sulfate 846 epitope (CS846), aggrecan fragments (AGC), disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and 5 (ADAMTS-5), as well as their natural inhibitor, known as tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), using immunoassay methods. Serum levels of CS846, AGC, ADAMTS-4, ADAMTS-5 and TIMP-3 were higher in female patients with RA before the treatment in comparison to healthy subjects. Ratio of ADAMTS-5 to TIMP-3 was significantly higher in RA women than in controls, whereas ADAMTS-4/TIMP-3 ratio did not differ from that in controls. During the anti-TNF-α therapy, the serum levels of 846 epitope increased, whereas levels of AGC decreased in female RA patients. Furthermore, 15 months of treatment with TNFαI downregulated serum levels of both ADAMTS, without any effect on TIMP-3 levels. These changes were accompanied by significantly reduced ratios of ADAMTS to TIMP-3. According to our results, anti-TNF-α therapy has a beneficial impact on aggrecan remodeling during RA.
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Geiter, Sabine, Markus Graf, Elin Tschokert, et al. "Values for ADAMTS-13 Activity, Antigen and Autoantibodies in Normal European Controls." Blood 114, no. 22 (2009): 4199. http://dx.doi.org/10.1182/blood.v114.22.4199.4199.
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Abstract Abstract 4199 INTRODUCTION In recent years, diagnostic tests for ADAMTS-13 and respective autoantibodies became available and are routinely used to support thrombotic thrombocytopenic purpura (TTP) diagnosis and therapy. ADAMTS-13 abnormalities have also been described in other pathological situations such as liver cirrhosis (Uemura, 2008), sepsis- induced DIC (Ono, 2006) or inflammatory bowel disease (Feys, 2009), where the relationship between ADAMTS13 parameters and state of disease is less clear than in TTP. A clear-cut distinction between normal and pathologic levels of ADAMTS-13 parameters (activity, antigen and autoantibodies) is only available in most TTP, with ADAMTS-13 activity levels < 10% and antibody titers well above normal levels. Pathological ranges for other diseases are not yet well defined. As normal ranges for ADAMTS-13 levels seem to be very broad, differentiation between normal and pathologic levels in cases other than TTP will depend on the size of the population used to establish the normal range and presumably also on age, gender, and likely also on other parameters present in this population. AIM The aim of this study was therefore to establish normal values for ADAMTS-13 parameters by analyzing normal populations in five different European laboratories using the same commercial assays. Material and Methods ADAMTS-13 autoantibodies were measured using the TECHNOZYM®ADAMTS-13 INH ELISA (anti-IgG). ADAMTS-13 activity and antigen concentrations were measured using TECHNOZYM®ADAMTS-13 ELISA, a combined assay for activity and antigen. Samples were frozen citrated plasma samples used in the respective laboratories as normal controls (approximately 40 in each laboratory; all together 193 normal controls). RESULTS The normal range for anti-ADAMTS-13 IgG was compared between the 5 different labs. For ADAMTS-13 INH, the median in these different populations varied between 6 and 9 U/ml which is well below the previously defined borderline value of 12 – 15 U/ml in this assay. The median for all samples was 6.7 U/ml; the number of “false-positives” (>15U/ml) varied from 5 to 10%. To analyze a possible age dependency, three groups were considered : <30 y.o., 31-50 y.o. and >50 y.o. No age dependent differences between these groups could be found (p>0.6). No significant differences were either found between male and female controls (p=0.55). For ADAMTS-13 activity and antigen only data from 140 normal subjects and 60 TTP patients are currently available. For normal subjects, the median for ADAMTS-13 activity was 103%, for antigen 101%. Both parameters showed a wide distribution of values between 53% and 205% for activity and 34% and 217% for antigen. In comparison, the median values in TTP patients were significantly lower (activity 12%, antigen 49%). Conclusion We can show that a substantial variation in normal values for ADAMTS-13 activity and antigen exists in normal subjects, while the range for ADAMTS-13 autoantibodies is rather narrow. All values in normal subjects are well separated from those obtained in TTP patients. The broad range of ADAMTS-13 activity and antigen in normal subjects has to be considered when these parameters are measured in diseases other than TTP. Disclosures: Geiter: Technoclone GmbH: Employment. Graf:Technoclone GmbH: Employment. Tschokert:Technoclone GmbH: Employment. Vetr:Technoclone GmbH: Employment.
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Borgi, Aida. "Congenital Thrombotic Thrombocytopenic Purpura: Atypical Presentation And First ADAMTS 13 Mutation In A Tunisian Child." Mediterranean Journal of Hematology and Infectious Diseases 5, no. 1 (2013): e2013041. http://dx.doi.org/10.4084/mjhid.2013.041.
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Background: Congenital deficiency of ADAMTS13 is characterized by systemic platelet clumping, hemolytic anemia and multiorgan failure. Although, more than 100 mutations have been reported, atypical clinical presentation may be involved in diagnostic difficulties. Case report: A 2 year old Tunisian child presented with chronic thrombopenic purpura which failed to respond to corticosteroids. Hemolytic anemia with schizocytes, occurred ten months later, with no previous history of diarrhea or any neurological abnormality. Renal function, coagulation screening tests and complement assay were normal. The count of platelet improved after fresh frozen infusion (FFP). Extensive investigations revealed a severe deficiency of ADAMTS 13 activity (level< 5%). Gene sequencing identified mutation in exon 18 of ADAMTS 13 gene. Prophylactic regimen with regular infusions of FFP was associated to favorable outcome. Conclusion: Early ADAMTS 13 activity testing and gene sequencing associated to precocious plasmatherapy are crucial to reduce morbidity and mortality of congenital TTP.
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Shieh, Huey-Sheng, Karl J. Mathis, Jennifer M. Williams, et al. "High Resolution Crystal Structure of the Catalytic Domain of ADAMTS-5 (Aggrecanase-2)." Journal of Biological Chemistry 283, no. 3 (2007): 1501–7. http://dx.doi.org/10.1074/jbc.m705879200.
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Aggrecanase-2 (a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5)), a member of the ADAMTS protein family, is critically involved in arthritic diseases because of its direct role in cleaving the cartilage component aggrecan. The catalytic domain of aggrecanase-2 has been refolded, purified, and crystallized, and its three-dimensional structure determined to 1.4Å resolution in the presence of an inhibitor. A high resolution structure of an ADAMTS/aggrecanase protein provides an opportunity for the development of therapeutics to treat osteoarthritis.
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Miwa, Hazuki E., Thomas A. Gerken, Tru D. Huynh, Lori R. Duesler, Meghan Cotter, and Thomas M. Hering. "Conserved sequence in the aggrecan interglobular domain modulates cleavage by ADAMTS-4 and ADAMTS-5." Biochimica et Biophysica Acta (BBA) - General Subjects 1790, no. 3 (2009): 161–72. http://dx.doi.org/10.1016/j.bbagen.2008.11.008.
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Lim, Ngee H., Masahide Kashiwagi, Robert Visse, et al. "Reactive-site mutants of N-TIMP-3 that selectively inhibit ADAMTS-4 and ADAMTS-5: biological and structural implications." Biochemical Journal 431, no. 1 (2010): 113–22. http://dx.doi.org/10.1042/bj20100725.
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We have reported previously that reactive-site mutants of N-TIMP-3 [N-terminal inhibitory domain of TIMP-3 (tissue inhibitor of metalloproteinases 3)] modified at the N-terminus, selectively inhibited ADAM17 (a disintegrin and metalloproteinase 17) over the MMPs (matrix metalloproteinases). The primary aggrecanases ADAMTS (ADAM with thrombospondin motifs) -4 and -5 are ADAM17-related metalloproteinases which are similarly inhibited by TIMP-3, but are poorly inhibited by other TIMPs. Using a newly developed recombinant protein substrate based on the IGD (interglobular domain) of aggrecan, gst-IGD-flag, these reactive-site mutants were found to similarly inhibit ADAMTS-4 and ADAMTS-5. Further mutations of N-TIMP-3 indicated that up to two extra alanine residues can be attached to the N-terminus before the Ki (app) for ADAMTS-4 and ADAMTS-5 increased to over 100 nM. No other residues tested at the [−1] position produced inhibitors as potent as the alanine mutant. The mutants N-TIMP-3(T2G), [−1A]N-TIMP-3 and [−2A]N-TIMP-3 were effective inhibitors of aggrecan degradation, but not of collagen degradation in both IL-1α (interleukin-1α)-stimulated porcine articular cartilage explants and IL-1α with oncostatin M-stimulated human cartilage explants. Molecular modelling studies indicated that the [−1A]N-TIMP-3 mutant has additional stabilizing interactions with the catalytic domains of ADAM17, ADAMTS-4 and ADAMTS-5 that are absent from complexes with MMPs. These observations suggest that further mutation of the residues of N-TIMP-3 which make unique contacts with these metalloproteinases may allow discrimination between them.
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Tsushima, Hidetoshi, Ken Okazaki, Mitsumasa Hayashida, Takahiro Ushijima та Yukihide Iwamoto. "CCAAT/enhancer binding protein β regulates expression of matrix metalloproteinase-3 in arthritis". Annals of the Rheumatic Diseases 71, № 1 (2011): 99–107. http://dx.doi.org/10.1136/annrheumdis-2011-200061.
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ObjectivesTo investigate whether CCAAT/enhancer binding protein β (C/EBPβ) mediates the expression of matrix metalloproteinase-3 (MMP-3) and aggrecanases in arthritis.MethodsLocalisation of C/EBPβ and MMP-3 in synovium and cartilage from patients with rheumatoid arthritis and osteoarthritis was determined by immunohistochemistry. Cell lines SW982, C28/I2 and human fibroblast-like synoviocytes stimulated by interleukin 1β (IL-1β) were subjected to western blotting and quantitative PCR. Overexpression of C/EBPβ by adenovirus was performed in cells and organ culture of normal cartilage. Knockdown of C/EBPβ by small interference RNA was performed in cells. Activity of the human MMP-3 and aggrecanase-2 ADAMTS-5 (a disintegrin and metalloproteinase with thrombospondin motifs) promoters was analysed by a luciferase assay. To determine whether C/EBPβ directly binds to the MMP-3 or ADAMTS-5 promoter,a chromatin immunoprecipitation assay was performed.ResultsImmunohistochemistry showed that C/EBPβ and MMP-3 were co-localised in arthritic synovium and cartilage. Western blots revealed increased C/EBPβ expression in cells treated with IL-1β. Expression of MMP-3, MMP-13 and ADAMTS-5 mRNA was significantly increased by the overexpression of C/EBPβ. C/EBPβ stimulated MMP-3 expression and induced matrix degradation in cartilage explants. C/EBPβ knockdown reduced MMP-3 and ADAMTS-5 expression. C/EBPβ stimulated the 2011 bp MMP-3 promoter and the 1768 bp ADAMTS-5 promoter in a dose-dependent manner. Deletion and mutation analysis of the MMP-3 promoter showed that the C/EBPβ core responsive element was located between −108 bp and −100 bp. The chromatin immunoprecipitation assay showed that C/EBPβ was directly bound to MMP-3 and ADAMTS-5 promoters.ConclusionsThese data demonstrate that C/EBPβ is involved in expression of MMP-3 and ADAMTS-5 in arthritic synovium and cartilage.
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Vankemmelbeke, Mireille N., Ingunn Holen, Anthony G. Wilson, et al. "Expression and activity of ADAMTS-5 in synovium." European Journal of Biochemistry 268, no. 5 (2001): 1259–68. http://dx.doi.org/10.1046/j.1432-1327.2001.01990.x.
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Nakada, Mitsutoshi, Hisashi Miyamori, Daisuke Kita, et al. "Human glioblastomas overexpress ADAMTS-5 that degrades brevican." Acta Neuropathologica 110, no. 3 (2005): 239–46. http://dx.doi.org/10.1007/s00401-005-1032-6.
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Salhotra, Amandeep, Santhosh Ambika, and Rekha Parameswaran. "Alloantibody Sensitization after PLASMA Exchanges for Relapsed Thrombotic Thrombocytopenic Purpura (TTP." Blood 112, no. 11 (2008): 4567. http://dx.doi.org/10.1182/blood.v112.11.4567.4567.
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Abstract Deficiency of ADAMTS-13, (A Disintegrin And Metalloprotease with 8 Thrombospondin like Domains), a Von Willebrandt Factor (VWF) cleaving protease, may be congenital (Upshaw Shulman syndrome) or acquired due to inhibitory autoantibodies and leads to the syndrome of Thrombotic Thrombocytopenic Purpura. Plasma exchange (PE) therapy is efficacious in therapy of TTP as it replenishes the deficient protease and at the same time removes the inhibitory antibody responsible for the enzyme deficiency. Few data exist effect of rising ADAMTS-13 inhibitor titers on the success of TTP therapy. We report a case of a 59 yr old African American woman who was diagnosed with TTP in October 2000 when she presented with altered mental status and focal weakness in right upper extremity. Initial labs showed Hemoglobin of 5.5 gm/dl, platelet count of 21,000/mm3, LDH of 4295. Peripheral smear showed moderate schistocytes and serum haptoglobin levels were decreased, renal function was normal. The patient received a total of 6 PE with FFP along with steroids and subsequently went into remission. The patient had a relapse after 10 months. She achieved remission with 5 PE. She was started on azathiaprine as an outpatient that was continued for five months. The patient remained asymptomatic for 5 years till her next relapse in the postoperative period after elective knee replacement surgery. The hospital course was complicated by development of transfusion related acute lung injury after receiving FFP. The patient again responded to PE (total 8 sessions) and IV steroids and went into remission. Prior to initiation of PE for this third relapse, tests showed ADAMTS -13 activity level was &lt;5% indicating severe deficiency of the enzyme; inhibitor titer was 3.2 Bethesda units (BU). Follow up testing after completion of PE and remission revealed persistently low ADAMTS 13 activity of &lt;5% with paradoxically higher inhibitor titers of 8 BU. Repeat testing after 16 months shows ADAMTS 13 activity of &lt;5% with inhibitor titers of 0.9 BU. CLINICAL COURSE ADAMTS 13 ADAMTS13 INHIBITOR IMMUNOSUPRESSION RELAPSE FREE PERIOD Third RELAPSE &lt;5% 3.2 BU STEROIDS+ PE 64 MONTHS REMISSION &lt;5% 8 BU AZATHIAPRINE 2 MONTHS REMISSION &lt;5% 0.9BU NONE 18 MONTHS Conclusion: Our patient developed rising titer of inhibitory antibodies to ADAMTS 13 post Plasma exchange during the second relapse of TTP; Pre and post plasma exchange autoantibody titers were 3.2 and 8.0 BU respectively. She was started on azathioprine after the third TTP relapse, which she took for 2 months and the therapy was then discontinued. She has remained in remission since then and repeat testing reveled ADAMTS 13 activity continues to be &lt;5% with the inhibitor titer decreasing to 0.9 BU. We postulate that the high inhibitor titers post plasma exchange could be the result of alloantibody formation as a result of FFP transfusions and the subsequent low level (0.9BU) inhibitor detected could be related to waning of alloantibody titers in the absence of further FFP exposure. Rising antibody titers post FFP exposure after PE therapy do not preclude a successful outcome with PE therapy with FFP replacement. Further study on the significance of rising antibody titers post PE therapy is required. Epitope mapping and idiotype analysis may be helpful in future studies.
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Scully, Marie, Richard Starke, Ian Mackie, and Samuel J. Machin. "Acute Idiopathic Thrombotic Thrombocytopenic Purpura: Predicting Relapse and Response to Treatment." Blood 108, no. 11 (2006): 1059. http://dx.doi.org/10.1182/blood.v108.11.1059.1059.
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Abstract Thrombotic thrombocytopenic purpura (TTP) is an acute, life threatening disorder. Idiopathic, antibody mediated disease accounts for 70% of cases of acute TTP, primarily IgG. We reviewed all cases of acute idiopathic TTP with serial samples available from diagnosis, relapse and in clinical remission to determine if there were factors predicting relapse and the benefit of Rituximab in preventing further episodes. All 25 cases presented with ADAMTS 13 activity <5%(NR 66–126%), during an acute TTP episode. Group A received Rituximab: 3 males and 10 females, the median age of presentation was 36.5 years (17–57 years), 2 were Afro Caribbean and 11 Caucasian. The median number of relapses prior to Rituximab were 4; 2 patients had>10 episodes each. A number of immunosuppressive/immunomodulatory therapies had been used in the past. Patients had clinical organ ischaemic episodes, including significant neurological events in all. In 8/13 patients, ADAMTS 13 activity was <5% through out clinical remission. Relapse was associated with increased IgG antibody levels. Since receiving Rituximab there has been an increase ADAMTS 13 activity within the normal range for 6 patients and > 25% for the remaining 2. In 3/13, ADAMTS 13 activity was maintained in the normal range by cyclosporine (CSA), stopping therapy associated with an acute relapse within 4–6 weeks. We substituted CSA for weekly Rituximab therapy (375mg/m2) over 4 weeks. In 2 patients, ADAMTS 13 activity was recordable in the normal range in clinical remission. A decrease activity and increase IgG antibody was associated with relapse. All patients had IgG antibodies to ADAMTS 13, which are negative post Rituximab therapy. Median follow-up post Rituximab is 18 months (8–33). In 3 patients, a second course of Rituximab was given between 18–24 months. Preceding a further course of Rituximab, ADAMTS 13 activity fell from the normal range to < 10% in all 3 and in 1 patient there was an associated significant rise in IgG anti-ADAMTS antibody level. In group B-no Rituximab therapy: 4 male and 8 females, median age at presentation-41.5 years (27–63); 3 Afro Caribbean, 1 Asian and 8 Caucasian. All presented with clinically significant organ ischaemia, including neurological features in 11/12. Seven cases had only 1 acute episode, 2 cases had 2 acute episodes and 3 had a chronic relapsing course. In 4 cases, ADAMTS 13 activity <5% during clinical remission; relapse associated with increased anti-ADAMTS IgG antibodies. In 5 patients, ADAMTS 13 activity increased to 25–50% in clinical remission. Three cases have a chronic relapsing course; 2 maintain ADAMTS 13 activity>50% on CSA. The 3rd has normal activity and negative IgG titres in remission. In conclusion: There were no specific phenotypic characteristics predictive of relapse. Of the patients in clinical remission with ADAMTS 13 activity <5%, the risk of relapse is doubled and is associated with increased IgG antibody titre. In patients who received Rituximab, normalisation of ADAMTS 13 activity can be attained. However, this is not always sustained and relapse in 2 patients post Rituximab was associated with a decrease in activity before an increase in antibody titre. Therefore, monitoring of ADAMTS 13 activity/IgG antibody to ADAMTS 13 following an episode of acute TTP can predict patients most likely to relapse. Elective therapy with Rituximab can prevent acute clinical features. Substitution of CSA in patients with chronic relapsing disease with Rituximab prevents the need for ongoing therapy.
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WESTLING, Jennifer, Paul E. GOTTSCHALL, Vivian P. THOMPSON, et al. "ADAMTS4 (aggrecanase-1) cleaves human brain versican V2 at Glu405-Gln406 to generate glial hyaluronate binding protein." Biochemical Journal 377, no. 3 (2004): 787–95. http://dx.doi.org/10.1042/bj20030896.
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Human brain tissue from cerebellum and hippocampus was obtained between 2 h and 24 h post mortem and, after extraction in the presence of proteinase inhibitors, proteoglycans were purified by anion-exchange chromatography. The versican component was characterized by Western analysis with antibodies to the N-terminal peptide (LF99), the N-terminal globular domain (12C5) and the two GAG (glycosaminoglycan) attachment regions (anti-GAG-α and anti-GAG-β). The results indicated that versican V2 is the major variant in all brain samples, and that it exists as the full-length form and also as at least six C-terminally truncated forms. The major immunoreactive species present is a 64 kDa product, which we identified by biochemical and immunological analysis as the brain protein previously termed GHAP (glial hyaluronate binding protein) [Perides, Lane, Andrews, Dahl and Bignami (1989) J. Biol. Chem. 264, 5981–5987]. Immunological analysis of purified human GHAP using a new anti-neoepitope antiserum (JSCNIV) showed that its C-terminal sequence is NIVSFE405, and digestion of human cerebellum proteoglycans with ADAMTS4 (aggrecanase-1, where ADAMTS, a disintegrin and metalloproteinase with thrombospondin-1-like motifs) indicated that GHAP is a product of cleavage of versican V0 or V2 at the Glu405–Gln406 bond. Since human cerebellum extracts contained multiple forms of ADAMTS4 protein on Western analysis, these data suggest that one or more members of the ‘aggrecanase’ group of the ADAMTS family (ADAMTS 1, 4, 5 and 9) are responsible for turnover of versican V2 in the adult human brain.
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Shu, Cindy, Carl Flannery, Christopher Little, and James Melrose. "Catabolism of Fibromodulin in Developmental Rudiment and Pathologic Articular Cartilage Demonstrates Novel Roles for MMP-13 and ADAMTS-4 in C-terminal Processing of SLRPs." International Journal of Molecular Sciences 20, no. 3 (2019): 579. http://dx.doi.org/10.3390/ijms20030579.
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Background: Cartilage regeneration requires a balance of anabolic and catabolic processes. Aim: To examine the susceptibility of fibromodulin (FMOD) and lumican (LUM) to degradation by MMP-13, ADAMTS-4 and ADAMTS-5, the three major degradative proteinases in articular cartilage, in cartilage development and in osteoarthritis (OA). Methods: Immunolocalization of FMOD and LUM in fetal foot and adult knee cartilages using an FMOD matrix metalloprotease (MMP)-13 neoepitope antibody (TsYG11) and C-terminal anti-FMOD (PR184) and anti-LUM (PR353) antibodies. The in vitro digestion of knee cartilage with MMP-13, A Disintegrin and Metalloprotease with Thrompospondin motifs (ADAMTS)-4 and ADAMTS-5, to assess whether FMOD and LUM fragments observed in Western blots of total knee replacement specimens could be generated. Normal ovine articular cartilage explants were cultured with interleukin (IL)-1 and Oncostatin-M (OSM) ± PGE3162689, a broad spectrum MMP inhibitor, to assess FMOD, LUM and collagen degradation. Results and Discussion: FMOD and LUM were immunolocalized in metatarsal and phalangeal fetal rudiment cartilages and growth plates. Antibody TsYG11 localized MMP-13-cleaved FMOD in the hypertrophic chondrocytes of the metatarsal growth plates. FMOD was more prominently localized in the superficial cartilage of normal and fibrillated zones in OA cartilage. TsYG11-positive FMOD was located deep in the cartilage samples. Ab TsYG11 identified FMOD fragmentation in Western blots of normal and fibrillated cartilage extracts and total knee replacement cartilage. The C-terminal anti-FMOD, Ab PR-184, failed to identify FMOD fragmentation due to C-terminal processing. The C-terminal LUM, Ab PR-353, identified three LUM fragments in OA cartilages. In vitro digestion of human knee cartilage with MMP-13, ADAMTS-4 and ADAMTS-5 generated FMOD fragments of 54, 45 and 32 kDa similar to in blots of OA cartilage; LUM was less susceptible to fragmentation. Ab PR-353 detected N-terminally processed LUM fragments of 39, 38 and 22 kDa in 65–80-year-old OA knee replacement cartilage. FMOD and LUM were differentially processed in MMP-13, ADAMTS-4 and ADAMTS-5 digestions. FMOD was susceptible to degradation by MMP-13, ADAMTS-4 and to a lesser extent by ADAMTS-5; however, LUM was not. MMP-13-cleaved FMOD in metatarsal and phalangeal fetal rudiment and growth plate cartilages suggested roles in skeletogenesis and OA pathogenesis. Explant cultures of ovine cartilage stimulated with IL-1/OSM ± PGE3162689 displayed GAG loss on day 5 due to ADAMTS activity. However, by day 12, the activation of proMMPs occurred as well as the degradation of FMOD and collagen. These changes were inhibited by PGE3162689, partly explaining the FMOD fragments seen in OA and the potential therapeutic utility of PGE3162689.
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Troeberg, Linda, Kazunari Fushimi, Simone D. Scilabra, et al. "The C-terminal domains of ADAMTS-4 and ADAMTS-5 promote association with N-TIMP-3." Matrix Biology 28, no. 8 (2009): 463–69. http://dx.doi.org/10.1016/j.matbio.2009.07.005.
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Song, Ruo-Hua, Micky D. Tortorella, Anne-Marie Malfait, et al. "Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5." Arthritis & Rheumatism 56, no. 2 (2007): 575–85. http://dx.doi.org/10.1002/art.22334.
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Dupuis, Loren E., E. Lockett Nelson, Brittany Hozik, et al. "Adamts5 −/− Mice Exhibit Altered Aggrecan Proteolytic Profiles That Correlate With Ascending Aortic Anomalies." Arteriosclerosis, Thrombosis, and Vascular Biology 39, no. 10 (2019): 2067–81. http://dx.doi.org/10.1161/atvbaha.119.313077.
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Objective: Investigate the requirement of Aggrecan (Acan) cleavage during aortic wall development in a murine model with ADAMTS (a disintegrin-like and metalloprotease domain with thrombospondin-type motifs) 5 deficiency and bicuspid aortic valves. Approach: Mice with altered extracellular matrix remodeling of proteoglycans will be examined for anomalies in ascending aortic wall development. Neo-epitope antibodies that recognize ADAMTS cleaved Acan fragments will be used to investigate the mechanistic requirement of Acan turnover, in aortic wall development. Results: Adamts5 −/− ;Smad2 +/− mice exhibited a high penetrance of aortic anomalies (n=17/17); Adamts5 −/− ;Smad2 +/− mice with bicuspid aortic valves (7/17) showed a higher number of anomalies than Adamts5 −/− ;Smad2 +/− mice with tricuspid aortic valves. Single mutant Adamts5 −/− mice also displayed a high penetrance of aortic anomalies (n=19/19) compared with wild type (n=1/11). Aortic anomalies correlated with Acan accumulation that was apparent at the onset of elastogenesis in Adamts5 −/− mice. Neo-epitope antibodies that recognize the initial amino acids in the Acan cleaved fragments neo-FREEE, neo-GLGS, and neo-SSELE were increased in the Adamts5 −/− aortas compared with WT. Conversely, neo-TEGE, which recognizes highly digested Acan core fragments, was reduced in Adamts5 −/− mice. However, mice containing a mutation in the TEGE 373 ↓ 374 ALGSV site, rendering it noncleavable, had low penetrance of aortic anomalies (n=2/4). Acan neo-DIPEN and neo-FFGVG fragments were observed in the aortic adventitia; Acan neo-FFGVG was increased abnormally in the medial layer and overlapped with smooth muscle cell loss in Adamts5 −/− aortas. Conclusions: Disruption of ADAMTS5 Acan cleavage during development correlates with ascending aortic anomalies. These data indicate that the mechanism of ADAMTS5 Acan cleavage may be critical for normal aortic wall development.
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Geiter, Sabine, Sebastién Colle, Paul A. Kyrle, Fritz Scheiflinger, Bernd R. Binder, and Helga Vetr. "Quantification of ADAMTS-13 Activity and Antigen from the Same Sample by a Newly Developed Combi-Actibind Assay (TECHNOZYM® ADAMTS-13)." Blood 108, no. 11 (2006): 1065. http://dx.doi.org/10.1182/blood.v108.11.1065.1065.
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Abstract Defects in activity and/or antigen levels of ADAMTS-13, the von Willebrand Factor (vWF) cleaving protease, are viewed as the main cause inducing the microvascular thrombotic disorder TTP (thrombotic thrombocytopenic purpura) that is in more than 90% of cases fatal if not treated early and appropriately. Malfunction of ADAMTS-13 with respect to cleave multimeric vWF can be caused by auto-antibodies directed against ADAMTS-13, by decreased presence of ADAMTS-13 in the circulation or by defective activity of ADAMTS-13. Therefore rapid and reliable diagnosis of ADAMTS-13 parameters is a clinical need. We present here a new assay for quantification of ADAMTS-13 activity and antigen levels based on ELISA format and thus suitable for fast and routine measurements. The method is based on the Actibind® technology, using a monoclonal antibody to capture ADAMTS-13 from plasma to a microtiter plate. Activity is then assayed by a fluorescent substrate. After removal of the substrate solution, antigen can be assayed by standard ELISA technology using a polyclonal antibody followed by a peroxidase labelled secondary antibody. Thus both parameters can be measured from the same sample consequently in the same assay allowing calculation of specific activities of ADAMTS-13. Dilutions of normal plasma (pool of 100 normal donors) were used as calibrators. The standard curve for the activity assay comprises a range from 3.7% to 100 % of normal plasma activity, thus samples of severe TTP (definition: activity below 5%) can be detected with sufficient sensitivity. 42 samples from TTP patients were tested in this new activity/antigen assay as well as in the TECHNOZYM ADAMTS-13 INH assay that allows determination of anti ADAMTS-13 auto antibodies. Using these two assays a significant negative correlation was found between ADAMTS-13 activity and the presence of autoantibodies, 82% of the samples with extremely low ADAMTS-13 activity (&lt;5%) had high levels of autoantibodies. A less stringent positive correlation was found between ADAMTS-13 antigen and ADAMTS-13 activity. Out of 30 samples with low ADAMTS-13 activity (&lt; 25%) 15 samples had antigen levels less than 50% of normal. Out of the 42 samples from TTP patients, 3 samples were found without auto antibodies but still low activity. 2 of these samples also had low antigen levels. Moreover, the TTP samples had significantly higher levels of vWF:CBA activity (p&lt;0.05) consistent with the presence of high molecular weight vWF. This combined new assay clearly adds to the diagnostic possibilities to differentiate patients with TTP with respect to defects in ADAMTS-13 function and antigen concentration. In addition, the results of this assay correlate with the clinical picture and the decreased functional activity of ADAMTS-13 leading to increased levels of vWF multimers and in turn platelet consumption.
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Böhm, Martina, Manuela Krause, Charis Von Auer, Wolfgang Miesbach, and Inge Scharrer. "The Frequency and the Significance of ADAMTS-13 Neutralising Inhibitors in 62 Patients with Non-Familial Thrombotic Thrombocytopenic Purpura." Blood 104, no. 11 (2004): 3945. http://dx.doi.org/10.1182/blood.v104.11.3945.3945.
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Abstract Neutralising inhibitors against ADAMTS-13 are detected in 51–67% of patients with Thrombotic Thrombocytopenic Purpura (TTP). These ADAMTS-13 inhibitors have not been very well characterised and the diagnostic or the prognostic value of these inhibitors is not established. In the present study, we measured ADAMTS-13 activity and the corresponding inhibitor titer in 96 samples from 62 patients with TTP at various stages of their disease. All patients presented with non-familial TTP. For patients with severe ADAMTS-13 activity without detectable inhibitor heritable ADAMTS-13 deficiency was excluded by either normalisation of ADAMTS-13 activity in remission or by detecting normal ADAMTS-13 activity in first degree family members. ADAMTS-13 activity was quantified by measuring the residual ristocetin cofactor activity of the substrate. The inhibitor against ADAMTS-13 was detected by mixing patient plasma, either neat or diluted, with normal plasma. The inhibitor concentration neutralising 50% of ADAMTS-13 activity in a 1:1 dilution of patient plasma with normal plasma was defined as 1 U/ml. Inhibitors were considered non-detectable (<0.4 U/ml), if residual ADAMTS-13 activity in the mixture was higher than 75%. Samples with ADAMTS-13 activity >6.25% were heat-inactivated (30 min at 56°C) before testing for inhibitory activity. We found severe ADAMTS-13 deficiency in 89% (24/27) of the samples from patients with acute untreated TTP. 87% (21/24) of these samples were positive for inhibitory activity. The inhibitor titer ranged from 0.4 to 62 U/ml with a median of 1 U/ml. One patient with acute TTP demonstrated ADAMTS-13 activity of 34% despite an inhibitor titer of 0.6 U/ml. The sensitivity of a positive inhibitor test for the diagnosis of TTP was thus 82%. The inhibitor titer before initiation of therapy could not be correlated with the platelet count, the CRP-level or the response to PE-therapy, if patients with an index episode and patients with a relapse were analysed separately. Severe ADAMTS-13 activity was detected in 15/31 samples collected from patients during plasma exchange therapy. 93% (14/15) of these samples were positive for an inhibitor with a titer ranging between 0.6 and 47 U/ml (median: 3 U/ml). 12 of 37 patients tested in remission presented with severe ADAMTS-13 deficiency, 6 of them were positive for inhibitory activity (range: 1–52 U/ml; median: 5 U/ml). The inhibitor titer for patients, which were analysed during acute untreated TTP as well as in remission (n=5), was notable not related to the stage of disease. Five patients with positive inhibitory activity at admission demonstrated mild ADAMTS-13 deficiency in remission without detectable inhibitor. In contrast, we detected inhibitory activity of 0,6–0,8 U/ml in 3 samples from two patients with measurable ADAMTS-13 activity. These low titer inhibitors were only detectable, if samples were heat inactivated before performing the inhibitor assay. Our data demonstrate, that inhibitors against ADAMTS-13 are very heterogeneous. It is highly suspected, that some of these inhibitors can either completely or partly neutralise ADAMTS-13 function in vivo without being detectable in vitro. Inhibitors against ADAMTS-13 might, on the other side, not always completely inhibit ADAMTS-13 function, since they can occur in patients with high residual ADAMTS-13 activity. Inhibitor titers show a wide variation and the clinical significance of the inhibitor titer before, during and after therapy needs to be further investigated.
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Mladenovic, Zvezdana, Anne-Sophie Saurel, Francis Berenbaum, and Claire Jacques. "Potential Role of Hyaluronic Acid on Bone in Osteoarthritis: Matrix Metalloproteinases, Aggrecanases, and RANKL Expression are Partially Prevented by Hyaluronic Acid in Interleukin 1-stimulated Osteoblasts." Journal of Rheumatology 41, no. 5 (2014): 945–54. http://dx.doi.org/10.3899/jrheum.130378.
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Objective.To determine the effect of hyaluronic acid (HA) on proteolytic enzymes and bone remodeling mediators induced by interleukin 1β (IL-1β) and related to cartilage catabolism in murine osteoblasts.Methods.Osteoblasts were obtained from Swiss mice and cultured for 3 weeks. HA-treated osteoblasts were incubated with 100 μg/ml HA during the last week of culture, then stimulated with IL-1β (10 ng/ml) for 24 h. The expression of matrix metalloproteinases 3 and 13 (MMP-3 and MMP-13), ADAMTS-4 and ADAMTS-5, tissue inhibitor of metalloproteinases (TIMP), osteoprotegerin, and receptor activator of nuclear factor-κB ligand (RANKL) was determined by real-time polymerase chain reaction. MMP-3 and MMP-13 release was assessed by Western blot analysis.Results.IL-1β increased the mRNA levels of MMP-3 and MMP-13 and ADAMTS-4 and ADAMTS-5 and release of MMP-3 and MMP-13. Seven days of HA treatment significantly prevented the IL-1β-increased mRNA levels of MMP-3 (−61%, p < 0.01), MMP-13 (−56%, p < 0.01), ADAMTS-4 (−58%, p < 0.05), ADAMTS-5 (−52%, p < 0.01), and RANKL (−49%, p < 0.05), but not TIMP. As well, IL-1β-induced production of MMP-3 and MMP-13 was inhibited, by 27% (p < 0.01) and 40% (p < 0.01), respectively.Conclusion.In an inflammatory context in murine osteoblasts, HA can inhibit the expression of MMP and ADAMTS. Because HA can counteract the production of these mediators in chondrocytes, its beneficial effect in osteoarthritis may be due to its action on cartilage and subchondral bone.