Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.6.4 (chondroitinase)
 2,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The capacity of various blood-borne cells, whether normal or malignant, to extravasate was found to correlate with heparanase-mediated degradation of HS in subendothelial ECM. This degradation was stimulated by proteases or plasminogen and inhibited by native heparin and by various modified nonanticoagulant species of heparin. These heparins also induced a marked reduction in tumor cell metastasis and autoimmune diseases in experimental animals. Heparanase-mediated degradation of HS in ECM also released EC growth factors that are stored in ECM, most likely by high affinity binding to HS. Such growth factors were extracted from subendothelial ECM synthesized in vitro and from basement membranes of the cornea in vivo, and are structurally and functionally related to bFGF;bFGF binds to ECM and is readily released by incubation with either HS, heparin or low MW heparin fragments as well as by various normal and malignant cells and by heparanase-mediated degradation of ECM HS. In contrast, there was little or no release of growth-promoting activity upon incubation of ECM with hyaluronic acid, chondroitin sulfate or chondroitinase ABC. A model is proposed suggesting that regulation of capillary growth and neovascular response may result from displacement of an angiogenic protein (bFGF) from its storage sites within basement membranes.
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PMID:Involvement of heparanase in tumor metastasis and angiogenesis. 246 49

The proposal that thrombin binds to dermatan sulphate chains of extracellular proteoglycans has been examined directly using the subendothelium of the rabbit aorta. Freshly excised aortas were de-endothelialized by balloon catheter in vitro and then incubated with 125I-thrombin to allow adsorption of 20-30 fmol of thrombin/cm2. Pretreatment of the subendothelium with FPR-thrombin or chondroitinase ABC partially inhibited thrombin binding, each by approximately 40-45%. The addition of dermatan sulphate inhibited, competitively, up to 50% of thrombin from binding to the subendothelium whereas chondroitin-4 or -6 sulphates had little or no effect. By contrast, protamine inhibited 90% of FPR-thrombin binding. Of subendothelium-bound thrombin, chondroitinase ABC released only a small proportion (3-12%) of bound thrombin but up to 44% of bound FPR-thrombin. It is concluded that, when 125I-thrombin is bound in vitro at a concentration of < 30 fmol/cm2 of aorta intima-media, approximately 50% of subendothelial 125I-thrombin is bound to dermatan sulphate chains of proteoglycan in the extracellular matrix. The possibility is discussed that dermatan sulphate chains may function as thrombin-binding loci to control or augment thrombin activity in the ECM of the injured vascular wall in vivo.
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PMID:Evidence for thrombin binding to dermatan sulphate sites in the rabbit aorta subendothelium in vitro. 814 86

Hepatocyte growth factor (HGF) promotes the growth not only of hepatocytes but also of several other types of cells such as cytotrophoblasts and endothelial cells. Recent studies have revealed that HGF is trapped in the extracellular (ECM) matrix through heparan sulphate in vivo, thereby acting as a mitogen for hepatocytes in cooperation with heparan sulphate. In this study, we detected HGF protein in chorionic tissue and placental tissue extracts, and found that HGF and heparan sulphate were co-distributed in the endothelial basement membrane and trophoblast basement membrane on immunohistochemical examination. The rates of DNA synthesis in primary cultured cytotrophoblasts and human umbilical vein endothelial cells (HUVEC) cultured on HGF-bound Matrigeltrade mark were 6-8 times those of control cytotrophoblasts and HUVEC. When Matrigeltrade mark dishes were pretreated with heparinase and heparitinase prior to binding of HGF, stimulation of DNA synthesis was markedly decreased. A considerable decrease in stimulation of DNA synthesis was observed following washing of HGF-bound Matrigeltrade mark with 1 m acetic acid, 1 m NaCl and 0.1 per cent trypsin, but not following treatment with chondroitinase ABC. These observations suggest that HGF can be trapped in ECM in vivo, thereby acting as a mitogen for cytotrophoblasts and placental vein endothelial cells in cooperation with heparan sulphate.
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PMID:Stimulation of DNA synthesis in trophoblasts and human umbilical vein endothelial cells by hepatocyte growth factor bound to extracellular matrix. 1052 23

It has been proposed that hyaluronan-binding proteoglycans play an important role as guiding cues during neural crest (NC) cell migration, but their precise function has not been elucidated. In this study, we examine the distribution, structure and putative role of the two major hyaluronan-binding proteoglycans, PG-M/versicans and aggrecan, during the course of avian NC development. PG-M/versicans V0 and V1 are shown to be the prevalent isoforms at initial and advanced phases of NC cell movement, whereas the V2 and V3 transcripts are first detected following gangliogenesis. During NC cell dispersion, mRNAs for PG-M/versicans V0/V1 are transcribed by tissues lining the NC migratory pathways, as well as by tissues delimiting nonpermissive areas. Immunohistochemistry confirm the deposition of the macromolecules in these regions and highlight regional differences in the density of these proteoglycans. PG-M/versicans assembled within the sclerotome rearrange from an initially uniform distribution to a preferentially caudal localization, both at the mRNA and protein level. This reorganization is a direct consequence of the metameric NC cell migration through the rostral portion of the somites. As suggested by previous in situ hybridizations, aggrecan shows a virtually opposite distribution to PG-M/versicans being confined to the perinotochordal ECM and extending dorsolaterally in a segmentally organized manner eventually to the entire spinal cord at axial levels interspacing the ganglia. PG-M/versicans purified from the NC migratory routes are highly polydispersed, have an apparent M(r) of 1,200-2,000 kDa, are primarily substituted with chondroitin-6-sulfates and, upon chondroitinase ABC digestion, are found to be composed of core proteins with apparent M(r )of 360-530, 000. TEM/rotary shadowing analysis of the isolated PG-M/versicans confirmed that they exhibit the characteristic bi-globular shape, have core proteins with sizes predicted for the V0/V1 isoforms and carry relatively few extended glycosaminoglycan chains. Orthotopical implantation of PG-M/versicans immobilized onto transplantable micromembranes tend to 'attract' moving cells toward them, whereas similar implantations of a notochordal type-aggrecan retain both single and cohorts of moving NC cells in close proximity of the implant and thereby perturb their spatiotemporal migratory pattern. NC cells fail to migrate through three-dimensional collagen type I-aggrecan substrata in vitro, but locomote in a haptotactic manner through collagen type I-PG-M/versican V0 substrata via engagement of HNK-1 antigen-bearing cell surface components. The present data suggest that PG-M/versicans and notochordal aggrecan exert divergent guiding functions during NC cell dispersion, which are mediated by both their core proteins and glycosaminoglycan side chains and may involve 'haptotactic-like' motility phenomena. Whereas aggrecan defines strictly impenetrable embryonic areas, PG-M/versicans are central components of the NC migratory pathways favoring the directed movement of the cells.
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PMID:Avian neural crest cell migration is diversely regulated by the two major hyaluronan-binding proteoglycans PG-M/versican and aggrecan. 1085 Nov 28

CNS lesions induce production of ECM molecules that inhibit axon regeneration. One major inhibitory family is the chondroitin sulfate proteoglycans (CSPGs). Reduction of their glycosaminoglycan (GAG) chains with chondroitinase ABC leads to increased axon regeneration that does not extend well past the lesion. Chondroitinase ABC, however, is unable to completely digest the GAG chains from the protein core, leaving an inhibitory "stub" carbohydrate behind. We used a newly designed DNA enzyme, which targets the mRNA of a critical enzyme that initiates glycosylation of the protein backbone of PGs, xylosyltransferase-1. DNA enzyme administration to TGF-beta-stimulated astrocytes in culture reduced specific GAG chains. The same DNA enzyme applied to the injured spinal cord led to a strong reduction of the GAG chains in the lesion penumbra and allowed axons to regenerate around the core of the lesion. Our experiments demonstrate the critical role of PGs, and particularly those in the penumbra, in causing regeneration failure in the adult spinal cord.
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PMID:A novel DNA enzyme reduces glycosaminoglycan chains in the glial scar and allows microtransplanted dorsal root ganglia axons to regenerate beyond lesions in the spinal cord. 1496 Jun 11

Chondroitin sulfate proteoglycans (CSPGs) are involved in several processes relevant to recovery of function after CNS damage. They restrict axon regeneration through their presence in glial scar tissue and plasticity through their presence in perineuronal nets (PNNs), affect memory through their effect on dendritic spines, and influence the inflammatory reaction. Much of our knowledge of these CSPG effects comes from digestion of their glycosaminoglycan chains by the enzyme chondroitinase ABC (ChABC). ChABC after spinal cord injury permits some axon regeneration and greatly increases plasticity through increased sprouting and through digestion of PNNs. When combined with appropriate rehabilitation, ChABC treatment can lead to considerable restoration of function. ChABC treatment of the perirhinal cortex greatly increases retention of object recognition memory. When applied to tauopathy animals that model Alzheimer's disease, ChABC digestion can restore normal object recognition memory. CSPGs in the adult CNS are found throughout the ECM, but 2% is concentrated in PNNs that surround GABAergic parvalbumin interneurons and other neurons. Knockout of the PNN-organizing protein Crtl1 link protein attenuates PNNs and leads to continued plasticity into adulthood, demonstrating that the CSPGs in PNNs are the key components in the control of plasticity. CSPGs act mainly through their sulfated glycosaminoglycan chains. A disulfated CS-E motif in these chains is responsible for binding of Semaphorin 3A to PNNs where it affects ocular dominance plasticity and probably other forms of plasticity. In addition OTX2 binds to CS-E motifs, where it can act on parvalbumin interneurons to maintain the PNNs.
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PMID:The extracellular matrix in plasticity and regeneration after CNS injury and neurodegenerative disease. 2589 Jan 39

We previously reported that a small, circumscribed region of the lateral hypothalamus, the anterior dorsal region (LHAad), stains heavily for PNNs and dense extracellular matrix (PNNs/ECM) with Wisteria floribunda agglutinin (WFA), and critically contributes to the acquisition of cocaine-induced conditioned place preference and cocaine self-administration. Here we tested the role of LHAad PNNs/ECM in cue-induced reinstatement in cocaine self-administering (SA) rats and identified how it is embedded in the circuitry of motivated behavior and drug reward. Degradation of PNNs/ECM in the LHAad using chondroitinase ABC (Ch-ABC) blocked the expression of cue-induced reinstatement of cocaine- but not sucrose-seeking behavior. We also identified for the first time the phenotype of LHAad PNN/ECM-surrounded neurons. LHAad neurons co-localized mainly with parvalbumin (PV+) and GABA. Predominant co-localization of WFA with VGLUT2 and GABA but not with GAD65/67 or glutamate indicates that the PNN/ECM-rich LHAad is predominantly GABAergic and receives dense glutamatergic input. The LHAad did not express significant amounts of melanin-concentrating hormone (MCH), orexin, or galanin; neuropeptides that regulate both food-induced and cocaine-induced behavior. In addition, retrobead injections demonstrated that the LHAad receives robust prelimbic prefrontal cortex (PFC) input and provides moderate input to the prelimbic PFC and ventral tegmental area (VTA), with no apparent input to the nucleus accumbens. In summary, the dense PNN/ECM zone in the LHAad embedded within the circuitry associated with reward pinpoints a novel region that controls the expression of cocaine-seeking behavior.
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PMID:Perineuronal nets in the lateral hypothalamus area regulate cue-induced reinstatement of cocaine-seeking behavior. 3086 69

Chondroitin sulfate (CS) is the most abundant glycosaminoglycan (GAG) in articular cartilage and the loss of CS-GAG occurs early in OA. As a major component of perichondral matrix interacting directly with chondrocytes, the active turnover of CS can affect to break the homeostasis of chondrocytes. Here we employ CS-based 3-dimensional (3D) hydrogel scaffold system to investigate how the degradation products of CS affect the catabolic phenotype of chondrocytes. The breakdown of CS-based ECM by the chondroitinase ABC (ChABC) resulted in a hypertrophy-like morphologic change in chondrocytes, which was accompanied by catabolic phenotypes, including increased MMP-13 and ADAMTS5 expression, nitric oxide (NO) production and oxidative stress. The inhibition of Toll-like receptor 2 (TLR2) or TLR4 with OxPAPC (TLR2 and TLR4 dual inhibitor) and LPS-RS (TLR4-MD2 inhibitor) ameliorated these catabolic phenotypes of chondrocytes by CS-ECM degradation, suggesting a role of CS breakdown products as damage-associated molecular patterns (DAMPs). As downstream signals of TLRs, MAP kinases, NF-kB, NO and STAT3-related signals were responsible for the catabolic phenotypes of chondrocytes associated with ECM degradation. NO in turn reinforced the activation of MAP kinases as well as NFkB signaling pathway. Thus, these results propose that the breakdown product of CS-GAG can recapitulate the catabolic phenotypes of OA.
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PMID:Degrading products of chondroitin sulfate can induce hypertrophy-like changes and MMP-13/ADAMTS5 production in chondrocytes. 3167 9