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See detailADAM metallopeptidase with thrombospondin type 1 motif 2 inactivation reduces the extent and stability of carbon tetrachloride-induced hepatic fibrosis in mice
Kesteloot, Frédéric ULg; Desmoulière, Alexis; Leclercq, Isabelle et al

in Hepatology (Baltimore, Md.) (2007), 46(5), 1620-1631

ADAMTS2 belongs to the "ADAM metallopeptidase with thrombospondin type I motif" (ADAMTS) family. Its primary function is to process collagen type I, II, III, and V precursors into mature molecules by ... [more ▼]

ADAMTS2 belongs to the "ADAM metallopeptidase with thrombospondin type I motif" (ADAMTS) family. Its primary function is to process collagen type I, II, III, and V precursors into mature molecules by excising the aminopropeptide. This process allows the correct assembly of collagen molecules into fibrils and fibers, which confers to connective tissues their architectural structure and mechanical resistance. To evaluate the impact of ADAMTS2 on the pathological accumulation of extracellular matrix proteins, mainly type I and III collagens, we evaluated carbon tetrachloride-induced liver fibrosis in ADAMTS2-deficient (TS2(-/-)) and wild-type (WT) mice. A single carbon tetrachloride injection caused a similar acute liver injury in deficient and WT mice. A chronic treatment induced collagen deposition in fibrous septa that were made of thinner and irregular fibers in TS2(-/-) mice. The rate of collagen deposition was slower in TS2(-/-) mice, and at an equivalent degree of fibrosis, the resorption of fibrous septa was slightly faster. Most of the genes involved in the development and reversion of the fibrosis were similarly regulated in TS2(-/-) and NW mice. Conclusion: These data indicate that the extent of fibrosis is reduced in TS2(-/-) mice in comparison with their WT littermates. Inhibiting the maturation of fibrillar collagens may be a beneficial therapeutic approach to interfering with the development of fibrotic lesions. [less ▲]

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See detailRegulation of procollagen amino-propeptide processing during mouse embryogenesis by specialization of homologous ADAMTS proteases: insights on collagen biosynthesis and dermatosparaxis
Le Goff, Carine; Somerville, Robert PT; Kesteloot, Frédéric ULg et al

in Development (2006), 133(8), 1587-1596

Mutations in ADAMTS2, a procollagen amino-propeptidase, cause severe skin fragility, designated as dermatosparaxis in animals, and a subtype of the Ehlers-Danlos syndrome (dermatosparactic type or VIIC ... [more ▼]

Mutations in ADAMTS2, a procollagen amino-propeptidase, cause severe skin fragility, designated as dermatosparaxis in animals, and a subtype of the Ehlers-Danlos syndrome (dermatosparactic type or VIIC) in humans. Not all collagen-rich tissues are affected to the same degree, which suggests compensation by the ADAMTS2 homologs ADAMTS3 and ADAMTS14. In situ hybridization of Adamts2, Adamts3 and Adamts14, and of the genes encoding the major. brillar collagens, Col1a1, Col2a1 and Col3a1, during mouse embryogenesis, demonstrated distinct tissue-specific, overlapping expression patterns of the protease and substrate genes. Adamts3, but not Adamts2 or Adamts14, was co-expressed with Col2a1 in cartilage throughout development, and with Col1a1 in bone and musculotendinous tissues. ADAMTS3 induced procollagen I processing in dermatosparactic. broblasts, suggesting a role in procollagen I processing during musculoskeletal development. Adamts2, but not Adamts3 or Adamts14, was co-expressed with Col3a1 in many tissues including the lungs and aorta, and Adamts2(-/-) mice showed widespread defects in procollagen III processing. Adamts2(-/-) mice had abnormal lungs, characterized by a decreased parenchymal density. However, the aorta and collagen fibrils in the aortic wall appeared normal. Although Adamts14 lacked developmental tissue-specific expression, it was co-expressed with Adamts2 in mature dermis, which possibly explains the presence of some processed skin procollagen in dermatosparaxis. The data show how evolutionarily related proteases with similar substrate preferences may have distinct biological roles owing to tissue specific gene expression, and provide insights into collagen biosynthesis and the pathobiology of dermatosparaxis. [less ▲]

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See detailDomains and maturation processes that regulate the activity of ADAMTS-2, a metalloproteinase cleaving the aminopropeptide of fibrillar procollagens types I-III and V
Colige, Alain ULg; Ruggiero, Florence; Vandenberghe, Isabel et al

in Journal of Biological Chemistry (2005), 280(41), 34397-34408

Processing of fibrillar collagens is required to generate collagen monomers able to self-assemble into elongated and cylindrical collagen fibrils. ADAMTS-2 belongs to the "A disintegrin and ... [more ▼]

Processing of fibrillar collagens is required to generate collagen monomers able to self-assemble into elongated and cylindrical collagen fibrils. ADAMTS-2 belongs to the "A disintegrin and metalloproteinase with thrombospondin type 1 motifs" (ADAMTS) family. It is responsible for most of the processing of the aminopropeptide of type I procollagen in the skin, and it also cleaves type II and type III procollagens. ADAMTS are complex secreted enzymes that are implicated in various physiological and pathological processes. Despite accumulating evidence indicating that their activity is regulated by ancillary domains, additional information is required for a better understanding of the specific function of each domain. We have generated 17 different recombinant forms of bovine ADAMTS-2 and characterized their processing, activity, and cleavage specificity. The results indicated the following: (i) activation of the ADAMTS-2 zymogen involves several cleavages, by proprotein convertases and C-terminal processing, and generates at least seven distinct processed forms; (ii) the C-terminal domain negatively regulates enzyme activity, whereas two thrombospondin type 1 repeats are enhancer regulators; (iii) the 104-kDa form displays the highest aminoprocollagen peptidase activity on procollagen type I; (iv) ADAMTS-2 processes the aminopropeptide of alpha1 type V procollagen homotrimer at the end of the variable domain; and (v) the cleaved sequence (PA) is different from the previously described sites ((P/A)Q) for ADAMTS-2, redefining its cleavage specificity. This finding and the existence of multiple processed forms of ADAMTS-2 strongly suggest that ADAMTS-2 may be involved in function(s) other than processing of fibrillar procollagen types I-III. [less ▲]

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See detailMutations near amino end of alpha 1(I) collagen cause combined osteogenesis imperfecta/Ehlers-Danlos syndrome by interference with N-propeptide processing
Cabral, Wayne A.; Makareeva, Elena; Colige, Alain ULg et al

in Journal of Biological Chemistry (2005), 280(19), 19259-19269

Patients with OI/EDS form a distinct subset of osteogenesis imperfecta (OI) patients. In addition to skeletal fragility, they have characteristics of Ehlers-Danlos syndrome (EDS). We identified 7 children ... [more ▼]

Patients with OI/EDS form a distinct subset of osteogenesis imperfecta (OI) patients. In addition to skeletal fragility, they have characteristics of Ehlers-Danlos syndrome (EDS). We identified 7 children with types III or IV OI, plus severe large and small joint laxity and early progressive scoliosis. In each child with OI/EDS, we identified a mutation in the first 90 residues of the helical region of α 1(I) collagen. These mutations prevent or delay removal of the procollagen N-propeptide by purified N-proteinase (ADAMTS-2) in vitro and in pericellular assays. The mutant pN-collagen which results is efficiently incorporated into matrix by cultured fibroblasts and osteoblasts and is prominently present in newly incorporated and immaturely cross-linked collagen. Dermal collagen fibrils have significantly reduced cross-sectional diameters, corroborating incorporation of pN-collagen into fibrils in vivo. Differential scanning calorimetry revealed that these mutant collagens are less stable than the corresponding procollagens, which is not seen with other type I collagen helical mutations. These mutations disrupt a distinct folding region of high thermal stability in the first 90 residues at the amino end of type I collagen and alter the secondary structure of the adjacent N-proteinase cleavage site. Thus, these OI/EDS collagen mutations are directly responsible for the bone fragility of OI and indirectly responsible for EDS symptoms, by interference with N-propeptide removal. [less ▲]

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See detailAcidic extracellular pH induces matrix metalloproteinase-9 expression in mouse metastatic melanoma cells through the phospholipase D-mitogen-activated protein kinase signaling
Kato, Y.; Lambert, Charles ULg; Colige, Alain ULg et al

in Journal of Biological Chemistry (2005), 280(12), 10938-10944

The extracellular pH (pHe) of tumor tissues is often acidic, which can induce the expression of several proteins. We previously showed that production of matrix metalloproteinase-9 (MMP-9) was induced by ... [more ▼]

The extracellular pH (pHe) of tumor tissues is often acidic, which can induce the expression of several proteins. We previously showed that production of matrix metalloproteinase-9 (MMP-9) was induced by culturing cells at acidic pHe (5.4-6.5). Here we have investigated the signal transduction pathway by which acidic pHe induces MMP-9 expression. We found that acidic pHe (5.9) activated phospholipase D (PLD), and inhibition of PLD activity by 1-butanol and Myr-ARF6 suppressed the acidic pHe-induced MMP-9 expression. Exogenous PLD, but not phosphatidylinositol-specific PLC or PLA(2), mimicked MMP-9 induction by acidic pHe. Western blot analysis revealed that acidic pHe increased the steady-state levels of phosphorylated extracellular signal-regulated kinases 1/2 and p38 and that the PLD inhibitors suppressed these increases. Using 5'-deletion mutant constructs of the MMP-9 promoter, we found that the acidic pHe-responsive region was located at nucleotide -670 to -531, a region containing the NF kappa B binding site. A mutation into the NF kappa B binding site reduced, but not completely, the acidic pHe- induced MMP-9 promoter activity, pand NF kappa B activity was induced by acidic pHe. Pharmacological inhibitors specific for mitogen-activated protein kinase kinase 1/2 (PD098059) and p38 (SB203580) attenuated the acidic pHe- induced NF kappa B activity and MMP-9 expression. These data suggest that PLD, mitogen-activated protein kinases (extracellular signal-regulated kinases 1/2 and p38), and NF kappa B mediate the acidic pHe signaling to induce MMP-9 expression. A transcription factor(s) other than NF kappa B may also be involved in the MMP-9 expression. [less ▲]

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See detailMMP-9 regulates both positively and negatively collagen gel contraction - A nonproteolytic function of MMP-9
Defawe, Olivier D; Kenagy, Richard D; Choi, Chun et al

in Cardiovascular Research (2005), 66(2), 402-409

Objective: Constrictive remodeling accounts for lumen loss in postangioplasty restenosis. Matrix metalloproteinase-9 (MMP-9) has been shown to prevent constrictive remodeling in vivo. To investigate ... [more ▼]

Objective: Constrictive remodeling accounts for lumen loss in postangioplasty restenosis. Matrix metalloproteinase-9 (MMP-9) has been shown to prevent constrictive remodeling in vivo. To investigate potential mechanisms for this observation, we investigated the role of MMP-9 in smooth muscle cell (SMC)-mediated collagen gel contraction, an in vitro model of constrictive remodeling. Methods: Fischer rat SMCs were stably transfected with a construct-expressing rat-MMP-9 under the control of a tetracycline (Tet)-off promoter. SMCs were seeded in type 1 collagen gels (2.4 mg/ml) in the presence or not of tetracycline (1 mu g/ml), and gel contraction was defined as the percentage of retraction of the collagen gel. The depletion of MMP-9 was obtained by using siRNA targeting MMP-9 mRNA or a blocking antibody. Results: Gel contraction was significantly reduced at all times when MMP-9 was overexpressed (Tet-) as compared with the control condition (Tet+). However, MMP-9 depletion of control (Tet+) SMCS (using siRNA or antibody) also inhibited gel contraction. To resolve the apparent discrepancy and determine if MMP-9 exerts a dose-dependent biphasic effect on gel contraction, conditioned medium and purified rat-MMP-9 were prepared. Gel contraction was significantly increased by addition of 0.8 mg/ml of MMP-9, while high concentrations of MMP-9 (>= 100 mg/ml) inhibited contraction. The addition of BB94 and TIMP-1 did not alter the inhibitory or stimulatory effect of MMP-9. Conclusions: Our data Suggest that MMP-9, independent of its proteolytic function, has a biphasic effect on SMC-mediated collagen gel contraction. Understanding the different roles of MMP-9 Should allow the development of better therapeutic strategies for restenotic vascular disease. (c) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved. [less ▲]

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See detailHistone deacetylase HDAC8 associates with smooth muscle alpha-actin and is essential for smooth muscle cell contractility
Waltregny, David ULg; Glenisson, Wendy; Tran, Syv Li et al

in FASEB Journal (2005), 19(8), 966-968

Although originally characterized as nuclear enzymes controlling the stability of nucleosomes, histone deacetylases (HDACs) may also exert their activity within the cytosol. Recently, we have demonstrated ... [more ▼]

Although originally characterized as nuclear enzymes controlling the stability of nucleosomes, histone deacetylases (HDACs) may also exert their activity within the cytosol. Recently, we have demonstrated that HDAC8, a class I HDAC, is a novel, prominently cytosolic marker of smooth muscle differentiation. As HDAC8 displays a striking stress fiber-like pattern of distribution and is coexpressed in vivo with smooth muscle alpha-actin (alpha-SMA) and smooth muscle myosin heavy chain, we have explored the possible participation of this HDAC in smooth muscle cytoskeleton regulation. Cell fractionation assays performed with primary human smooth muscle cells (HSMCs) showed that HDAC8, in contrast to HDAC1 and HDAC3, was enriched in cytoskeleton-bound protein fractions and insoluble cell pellets, suggesting an association of HDAC8 with the cystoskeleton. Coimmunoprecipitation experiments using HSMCs, NIH-3T3 cells, and human prostate tissue lysates further demonstrated that HDAC8 associates with alpha-SMA but not with beta-actin. HDAC8 silencing through RNA interference strongly reduced the capacity of HSMCs to contract collagen lattices. Mock transfections had no effect on HSMC contractily, and transfections with small interfering RNAs (siRNAs) specific for HDAC6, a cytosolic HDAC that functions as an alpha-tubulin deacetylase, resulted in a weak contraction inhibition. Although mock- and HDAC6 siRNA-transfected HSMCs showed no noticeable morphological changes, HDAC8 siRNA-transfected HSMCs displayed a size reduction with diminished cell spreading after replating. Altogether, our findings indicate that HDAC8 associates with the smooth muscle actin cytoskeleton and may regulate the contractile capacity of smooth muscle cells. [less ▲]

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See detailADAMTS-2, a metalloproteinase containing a disintegrin domain and thrombospondin type I repeats, a new regulator of angiogenesis
Dubail, Johanne ULg; Kesteloot, Frédéric ULg; Motte, Patrick ULg et al

in Journal of Vascular Research (2005), 42(Suppl. 2), 76

Enzymes of the ADAMTS family are closely related to MMPs and ADAMs. They further contain specific domains, such as the “ThromboSpondin type I” (TSP1) repeats able to strongly repress angiogenesis. The ... [more ▼]

Enzymes of the ADAMTS family are closely related to MMPs and ADAMs. They further contain specific domains, such as the “ThromboSpondin type I” (TSP1) repeats able to strongly repress angiogenesis. The primary function of ADAMTS-2 is to process procollagen type I, II, III and V into mature molecules by excising the amino-propeptide. We further hypothesized that it could modulate angiogenesis through its TSP1 repeats. Recombinant ADAMTS-2 induced morphological changes in HUVEC and HMEC cultured on gelatin, collagen and fibronectin. It also significantly reduced their proliferation, attachment and spreading. Similar effects were observed when using inactive ADAMTS-2 mutated at the Zn++-binding catalytic site. ADAMTS-2 did not alter the initial steps of formation of capillary-like structures by HUVEC in vitro. However, these structures appeared more rapidly disrupted in presence of ADAMTS-2 than in control conditions. Immunostaining with monoclonal antibodies against ADAMTS-2 indicate that it is tightly immobilized at the endothelial cell surface by an heparin-sensitive binding. With the aim to identify mechanism(s)leading to the modulation of angiogenesis by ADAMTS-2, we investigated various signalling pathways critical for EC. Phosphorylation status of FAK was not altered by ADAMTS-2 while a downregulation of phosphorylation of p42/44 MAPK was observed. Our data suggest that ADAMTS-2 reduces angiogenesis by regulating endothelial cell adhesion and proliferation, and by alteration of the stability of the capillary-like structures. These effects do not seem to be mediated by an integrin-dependent signaling pathway. Choroidal neovascularization induced in TS2+/+ or TS2-/- mice by LASER burns was used as in vivo model. Several genes involved in the healing and angiogenesis processes (fibrillar collagens, VEGF, TGF, CTGF, …) were not differently regulated in TS2+/+ and TS2-/- mice 5 days after the LASER impact. Wound capillaries visualized by confocal microscopy after FITC-conjugated dextran injection, were significantly increased (p<0,05) in TS2-/- mice suggesting an increased angiogenic response in the KO animals. The results obtained in in vivo and in vitro models indicate that ADAMTS-2 is involved in the control of angiogenesis. Additional investigations are being performed to determine which domain(s) of the molecule is (are) antiangiogenic and to identify the mechanism(s) underlying this regulatory function. [less ▲]

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See detailGradient of proteolytic enzymes, their inhibitors and matrix proteins expression in a ruptured abdominal aortic aneurysm
Defawe, O. D.; Colige, Alain ULg; Lambert, Charles ULg et al

in European Journal of Clinical Investigation (2004), 34(7), 513-514

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See detailChanges in matrix gene and protein expressions after single or repeated exposure to one minimal erythemal dose of solar-simulated radiation in human skin in vivo
Seite, S.; Colige, Alain ULg; Deroanne, Christophe ULg et al

in Photochemistry and Photobiology (2004), 79(3), 265-271

Damage to the skin extracellular matrix (ECM) is the hallmark of long-term exposure to solar UV radiation. The aim of our study was to investigate the changes induced in unexposed human skin in vivo after ... [more ▼]

Damage to the skin extracellular matrix (ECM) is the hallmark of long-term exposure to solar UV radiation. The aim of our study was to investigate the changes induced in unexposed human skin in vivo after single or repeated (five times a week for 6 weeks) exposure to I minimal erythemal dose (MED) of UV solar-simulated radiation. Morphological and biochemical analyses were used to evaluate the structural ECM components and the balance between the degrading enzymes and their physiologic inhibitors. A three-fold increase in matrix metalloproteinase 2 messenger RNA (mRNA) (P < 0.02, unexposed versus exposed) was observed after both single and repeated exposures. Fibrillin 1 mRNA level was increased by chronic exposure (P < 0.02) and unaltered by a single MED. On the contrary, a single MED significantly enhanced mRNA levels of interleukin-la (IL-1alpha), IL-1beta (P < 0.02) and plasminogen activator inhibitor-1 (P < 0.05). Immunohistochemistry demonstrated a significant decrease in Type-I procollagen localized just below the dermal-epidermal junction in both types of exposed sites. At the same location, the immunodetected tenascin was significantly enhanced, whereas a slight increase in Type-III procollagen deposits was also observed in chronically exposed areas. Although we were unable to observe any change in elastic fibers in chronically exposed buttock skin, a significant increase in lysozyme and alpha-1 antitrypsin deposits on these fibers was observed. These results demonstrate the existence of a differential regulation, after chronic exposure compared with an acute one, of some ECM components and inflammatory mediators. [less ▲]

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See detailProcollagen III N-endopeptidase.
Colige, Alain ULg

in Barrett, Alan J; Rawlings, Neil D.; Woessner, Fred J. (Eds.) Handbook of proteolytic enzymes, 2nd Edition. - Volume 1 - (2004)

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See detailProcollagen N-endopeptidase, ADAMTS2.
Colige, Alain ULg

in Barrett, Alan J.; Rawlings, Neil D; Woessner, Fred J. (Eds.) Handbook of proteolytic enzymes, 2nd Edition. - Volume 1 (2004)

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See detailMECHANICAL STRAIN MODULATES MONOCYTE CHEMOTACTIC PROTEIN-1 AND IL-1BETA EXPRESSION BY CULTURED HUMAN AORTIC SMOOTH MUSCLE CELLS
Defawe, Olivier; Colige, Alain ULg; Deroanne, Christophe ULg et al

in Cardiovascular Pathology (2004), 13(3 suppl), 189

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See detailEffect of ADAMTS-2, a metalloproteinase containing a disintegrin domain and thrombospondin type I repeats, during angiogenesis in vitro and in vivo
Dubail, Johanne ULg; Kesteloot, Frédéric ULg; Motte, Patrick ULg et al

in Angiogenesis (2004), 7(2), 172

Formation of new blood vessels (angiogenesis) is a key step during the development of various pathologies, including cancer. Enzymes of the ADAMTS family are closely related to MMPs and ADAMs. They ... [more ▼]

Formation of new blood vessels (angiogenesis) is a key step during the development of various pathologies, including cancer. Enzymes of the ADAMTS family are closely related to MMPs and ADAMs. They further contain specific domains, such as the ‘‘Thrombospondin type I’’ (TSP1) repeats, that are able to strongly repress angiogenesis, as described for thrombospondin-1 and -2, and for ADAMTS-1 and -8. The primary function of ADAMTS-2 is to process collagen type I, II and III precursors into mature molecules by excising the aminopropeptide. We further hypothesized that it could modulate angiogenesis through its TSP1 repeats. This hypothesis was investigated using different in vitro experimental models of angiogenesis. Recombinant ADAMTS-2 induced morphological changes in human umbilical vein endothelial cells (HUVEC) and human microvessel endothelial cells (HMEC), and significantly reduced their proliferation, attachment and spreading. Similar effects were observed when using inactive ADAMTS-2 mutated at the Zn2+-binding catalytic site. ADAMTS-2 did not alter the initial steps of formation of capillary-like structures by HUVEC in vitro. However, these structures appeared much less stable and were more rapidly disrupted in presence of ADAMTS-2 than in control conditions. ADAMTS-2 was also tested in an ex vivo angiogenesis model using aortic rings from rats and mice, wild type or KO for ADAMTS-2. Outgrowth of capillaries was slightly increased from aortas of ADAMTS-2 KO mice (TS2-/-) as compared to aortas from control animals (TS2+/+), while addition of full size recombinant ADAMTS-2 reduced the formation of capillary structures from rat aortas, suggesting its anti-angiogenic activity. Choroidal neovascularization induced in TS2+/+ or TS2-/- mice by LASER burns was used as in vivo model to confirm the in vitro and ex vivo results. Several genes involved in the healing and angiogenesis processes (fibrillar collagens, VEGF, TGF-beta and CTGF) were not differently regulated in TS2+/+ and TS2-/- mice at 5 days. [less ▲]

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See detailNovel types of mutation responsible for the dermatosparactic type of Ehlers-Danlos syndrome (Type VIIC) and common polymorphisms in the ADAMTS2 gene.
Colige, Alain ULg; Nuytinck, Lieve; Hausser, Ingrid et al

in The Journal of investigative dermatology (2004), 123(4), 656-63

Ehlers-Danlos syndrome (EDS) type VIIC, or dermatosparactic type, is a recessively inherited connective tissue disorder characterized, among other symptoms, by an extreme skin fragility resulting from ... [more ▼]

Ehlers-Danlos syndrome (EDS) type VIIC, or dermatosparactic type, is a recessively inherited connective tissue disorder characterized, among other symptoms, by an extreme skin fragility resulting from mutations inactivating ADAMTS-2, an enzyme excising the aminopropeptide of procollagens type I, II, and III. All previously described mutations create premature stop codons leading to a marked reduction in the level of mRNA. In this study, we analyzed the ADAMTS2 cDNA sequences from five patients displaying clinical and/or biochemical features consistent with a diagnosis of either typical or potentially mild form of EDS type VIIC. Three different alterations were detected in the two patients with typical EDS type VIIC. The first patient was homozygous for a genomic deletion causing an in-frame skipping of exons 3-5 in the transcript. In the second patient, the allele inherited from the mother lacks exon 3, generating a premature stop codon, whereas the paternal allele has a genomic deletion resulting in an in-frame skipping of exons 14-16 at the mRNA level. Although the exons 3-5 or 14-16 encode protein domains that have not been previously recognized as crucial for ADAMTS-2 activity, the aminoprocollagen processing was strongly impaired in vitro and in vivo, providing evidence for the requirement of these domains for proper enzyme function. The three other patients with a phenotype with some resemblance to EDS type VIIC only had silent and functionally neutral variations also frequently found in a normal population. [less ▲]

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See detailThe natural history, including orofacial features of three patients with Ehlers-Danlos syndrome, dermatosparaxis type (EDS type VIIC).
Malfait, Fransiska; De Coster, Peter; Hausser, Ingrid et al

in American Journal of Medical Genetics. Part A (2004), 131(1), 18-28

Ehlers-Danlos syndrome (EDS) dermatosparaxis type (type VIIC) and the related disease of cattle dermatosparaxis, are recessively inherited connective tissue disorders, caused by a deficient activity of ... [more ▼]

Ehlers-Danlos syndrome (EDS) dermatosparaxis type (type VIIC) and the related disease of cattle dermatosparaxis, are recessively inherited connective tissue disorders, caused by a deficient activity of procollagen I N-proteinase, the enzyme that excises the N-terminal propeptide in procollagen type I, type II, and type III. Although well documented in cattle, to date only seven human cases have been recorded, most of them aged under 2 years. We document the natural history of three patients with EDS dermatosparaxis type, two of whom have been reported before the age of 2 years, and one new patient. The phenotype of the patients, and especially the facial resemblance, is striking, making this a clinically recognizable condition. The most consistent anomalies during the first years of life are premature rupture of the membranes, extreme skin fragility and easy bruising, large fontanels, blue sclerae, puffy eyelids, micrognathia, umbilical hernia, and short fingers. Joint hypermobility becomes more important with age. The children are at risk for rupture of internal organs due to soft tissue fragility, as is illustrated by different internal events in two of the three patients described here. Orofacial features include micrognathia, a frontal open bite, and gingival hyperplasia with varying degrees of hyperkeratosis. The deciduous dentition shows abnormal morphology of the molars, obliteration of the tooth pulp, and severe enamel attrition. The permanent dentition shows agenesis and microdontia of several teeth. Tooth discoloration, dysplastic roots, and tooth pulp obliteration are present in a restricted number of permanent teeth. [less ▲]

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See detailEvaluation of the function of ADAMTS-2, a metalloproteinase containing a disintegrin domain and thrombospondin type I repeats, during angiogenesis in vitro and in vivo
Kesteloot, Frédéric ULg; Lapière, Charles M; Colige, Alain ULg et al

in Acta Clinica Belgica (2004), 59(2), 120

Angiogenesis is required for development, growth, tissue remodeling, and wound healing. Pathologies such as diabetic retinopathy, rheumatoid arthritis and cancer would benefit from therapies controlling ... [more ▼]

Angiogenesis is required for development, growth, tissue remodeling, and wound healing. Pathologies such as diabetic retinopathy, rheumatoid arthritis and cancer would benefit from therapies controlling and reducing angiogenesis. Enzymes of the ADAMTS family are closely related to MMPs and ADAMs. They contain however some specific features, such as a variable number of domains known as “ThromboSpondin type I repeat” (TSPI). ADAMTS-1 and -8 are 20-fold more anti-angiogenic than angiostatin and endostatin, two potent inhibitors of angiogenesis. The primary function of ADAMTS-2 is the maturation of collagen type I and II molecules by excising the amino-propeptide. In addition, ADAMTS-2 could also modulate angiogenesis, as it contains the same sequences than those responsible for the anti-angiogenic activity of ADAMTS-1 and -8. This hypothesis was investigated in vitro in different experimental models such as cell proliferation and formation of capillary structures by human endothelial cells. An ex vivo angiogenesis model was also used. It consists in mice or rat aorta pieces embedded in a collagen gel in order to allow the growth of capillaries from the vascular endothelium. As compared to control mice (TS2+/+), angiogenesis was slightly increased, in absence of ADAMTS-2, from aortas of ADAMTS-2 KO mice (TS2-/-). Using rat aortas, addition of recombinant ADAMTS-2 reduced the formation of capillary structure, also confirming the anti-angiogenic activity of ADAMTS-2. Finally, an in vivo model of angiogenesis was also used. Biocompatible sponges (Ivalon) were implanted under the skin of TS2+/+ or TS2-/- mice in order to evaluate the formation of capillaries in the granulation tissue invading the sponge. In absence of ADAMTS-2, angiogenesis and granulation tissue formation were both reduced. Additional investigations are being performed in order to identify the underlying mechanism(s) inducing these modifications. [less ▲]

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See detailExpression pattern of metalloproteinases and tissue inhibitors of matrix-metalloproteinases in cycling human endometrium
Goffin, Frédéric ULg; Munaut, Carine ULg; Frankenne, Francis et al

in Biology of Reproduction (2003), 69(3), 976-984

The cyclic growth, differentiation, and cell death of endometrium represents the most dynamic example of steroid-driven tissue turnover in human adults. Key effectors in these processes-matrix ... [more ▼]

The cyclic growth, differentiation, and cell death of endometrium represents the most dynamic example of steroid-driven tissue turnover in human adults. Key effectors in these processes-matrix metalloproteinases (MMPs) and their specific inhibitors (TIMPs)-are regulated by ovarian steroids and, locally, by cytokines. We used reverse transcription-polymerase chain reaction to evaluate the expression of both transcriptionally regulated molecules such as estrogen receptor-alpha, progesterone receptor, and prolactin and a large array of MMPs and TIMPs (MMP-1, -2, -3, -7, -8, -9, -11, -12, -19, -26, MT1-MMP, MT2-MMP, MT3-MMP, TIMP-1, -2, -3). Altogether, three distinct patterns of MMP and two patterns of TIMP expression were detected in cycling endometrium: 1). MMPs restricted to the menstrual period (MMPs-1, -3, -8, -9, -12); 2). MMPs and TIMPs expressed throughout the cycle (MMP-2, MT1-MMP, MT2-MMP, MMP-19, TIMP-1, and TIMP-2); 3). MMPs predominantly expressed during the proliferative phase (MMP-7, MMP-11, MMP-26, and MT3-MMP); and 4). TIMP-3, which, contrary to the other TIMPs, shows significant modulations, with maximum expression during the late secretory and menstrual phases. These specific patterns of MMP expression associated with each phase of the cycle may point to specific roles in the processes of menstruation, housekeeping activities, angiogenesis, tissue growth, and extracellular matrix remodeling. [less ▲]

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See detailTIMP-2 and PAI-1 mRNA levels are lower in aneurysmal as compared to athero-occlusive abdominal aortas.
Defawe, Olivier D; Colige, Alain ULg; Lambert, Charles ULg et al

in Cardiovascular Research (2003), 60(1), 205-13

OBJECTIVE: Significant alterations of the vascular wall occurs in abdominal aortic aneurysm (AAA) and atherosclerotic occlusive disease (AOD) that ultimately may lead to either vascular rupture or ... [more ▼]

OBJECTIVE: Significant alterations of the vascular wall occurs in abdominal aortic aneurysm (AAA) and atherosclerotic occlusive disease (AOD) that ultimately may lead to either vascular rupture or obstruction. These modifications have been ascribed to one or a group of proteases, their inhibitors or to the matrix macromolecules involved in the repair process without considering the extent of the observed variations. METHODS: The mRNA steady-state level of a large spectrum of proteolytic enzymes (matrix metalloproteinases: MMP-1, -2, -3, -8, -9, -11, -12, -13, -14; urokinase plasminogen activator: u-PA), their physiological inhibitors (tissue inhibitors of MMPs: TIMP-1, -2, -3; plasminogen activator inhibitor: PAI-1) and that of structural matrix proteins (collagens type I and III, decorin, elastin, fibrillins 1 and 2) was determined by RT-PCR made quantitative by using a synthetic RNA as internal standard in each reaction mixture. The profile of expression was evaluated in AAA (n=7) and AOD (n=5) and compared to non-diseased abdominal (CAA, n=7) and thoracic aorta (CTA, n=5). RESULTS: The MMPs -8, -9, -12 and -13 mostly associated with inflammatory cells were not or barely detected in CAA and CTA while they were largely and similarly expressed in AAA and AOD. Expression of protease inhibitors or structural proteins were only slightly increased in both pathological conditions with the exception of elastin which was reduced. The main significant difference between AAA and AOD was a lower expression of TIMP-2 and PAI-1 in the aneurysmal lesions. CONCLUSIONS: The remodeling of the aortic wall in AAA and AOD involves gene activation of a large and similar spectrum of proteolytic enzymes while the expression of two physiological inhibitors, TIMP-2 and PAI-1, is significantly lower in AAA compared to AOD. The repair process in the aneurysmal disease seems similar to that of the occlusive disease. [less ▲]

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See detailType I collagen triplet duplication mutation in lethal osteogenesis imperfecta shifts register of alpha chains throughout the helix and disrupts incorporation of mutant helices into fibrils and extracellular matrix.
Cabral, Wayne A; Mertts, Marianna V; Makareeva, Elena et al

in Journal of Biological Chemistry (2003), 278(12), 10006-12

The majority of collagen mutations causing osteogenesis imperfecta (OI) are glycine substitutions that disrupt formation of the triple helix. A rare type of collagen mutation consists of a duplication or ... [more ▼]

The majority of collagen mutations causing osteogenesis imperfecta (OI) are glycine substitutions that disrupt formation of the triple helix. A rare type of collagen mutation consists of a duplication or deletion of one or two Gly-X-Y triplets. These mutations shift the register of collagen chains with respect to each other in the helix but do not interrupt the triplet sequence, yet they have severe clinical consequences. We investigated the effect of shifting the register of the collagen helix by a single Gly-X-Y triplet on collagen assembly, stability, and incorporation into fibrils and matrix. These studies utilized a triplet duplication in COL1A1 exon 44 that occurred in the cDNA and gDNA of two siblings with lethal OI. The normal allele encodes three identical Gly-Ala-Hyp triplets at aa 868-876, whereas the mutant allele encodes four. The register shift delays helix formation, causing overmodification. Differential scanning calorimetry yielded a decrease in T(m) of 2 degrees C for helices with one mutant chain and a 6 degrees C decrease in helices with two mutant chains. An in vitro binary co-processing assay of N-proteinase cleavage demonstrated that procollagen with the triplet duplication has slower N-propeptide cleavage than in normal controls or procollagen with proalpha1(I) G832S, G898S, or G997S substitutions, showing that the register shift persists through the entire helix. The register shift disrupts incorporation of mutant collagen into fibrils and matrix. Proband fibrils formed inefficiently in vitro and contained only normal helices and helices with a single mutant chain. Helices with two mutant chains and a significant portion of helices with one mutant chain did not form fibrils. In matrix deposited by proband fibroblasts, mutant chains were abundant in the immaturely cross-linked fraction but constituted a minor fraction of maturely cross-linked chains. The profound effects of shifting the collagen triplet register on chain interactions in the helix and on fibril formation correlate with the severe clinical consequences. [less ▲]

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