Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.2.1.36 (hyaluronidase)
 4,606 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyaluronan (hyaluronic acid) is a high-molecular-mass polysaccharide found in the extracellular matrix, especially of soft connective tissues. It is synthesized in the plasma membrane of fibroblasts and other cells by addition of sugars to the reducing end of the polymer, whereas the nonreducing end protrudes into the pericellular space. The polysaccharide is catabolized locally or carried by lymph to lymph nodes or the general circulation, from where it is cleared by the endothelial cells of the liver sinusoids. The overall turnover rate is surprisingly rapid for a connective tissue matrix component (t1/2 0.5 to a few days). Hyaluronan has been assigned various physiological functions in the intercellular matrix, e.g., in water and plasma protein homeostasis. Hyaluronan production increases in proliferating cells and the polymer may play a role in mitosis. Extensive hyaluronidase-sensitive coats have been identified around mesenchymal cells. They are either anchored firmly in the plasma membrane or bound via hyaluronan-specific binding proteins (receptors). Such receptors have now been identified on many different cells, e.g., the lymphocyte homing receptor CD 44. Interaction between a hyaluronan receptor and extracellular polysaccharide has been connected with locomotion and cell migration. Hyaluronan seems to play an important role during development and differentiation and has other cell regulatory activities. Hyaluronan has also been recognized in clinical medicine. A concentrated solution of hyaluronan (10 mg/ml) has, through its tissue protective and rheological properties, become a device in ophthalmic surgery. Analysis of serum hyaluronan is promising in the diagnosis of liver disease and various inflammatory conditions, e.g., rheumatoid arthritis. Interstitial edema caused by accumulation of hyaluronan may cause dysfunction in various organs.
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PMID:Hyaluronan. 156 92

A monoclonal antibody, MAb IVd4, that recognizes hyaluronan-binding protein (HABP) from chick embryo brain has been produced and characterized. By immunoblotting, MAb IVd4 was shown to recognize three proteins in chick embryo brain of molecular weight 93, 90, and 69 kDa; this interaction was inhibited by addition of hyaluronan hexasaccharides. Overlay of transblots with [3H]hyaluronan showed binding to proteins of similar molecular weight. MAb IVd4 blocked binding of [3H]hyaluronan to brain HABP and to simian virus-transformed 3T3 cells, indicating a possible relationship with the 85-kDa hyaluronan receptor of these cells. The distribution of HABP during early brain development was analyzed by immunohistochemistry. Immunoreactivity was uniform in newly formed neuroectoderm but became more concentrated in the roof of the brain during the second day of embryonic development. As the neuroectoderm becomes layered, the HABP was increasingly restricted to the forming plexiform layer, an area enriched in neural cell processes. Immunoreactivity was greatly enhanced by pretreatment of tissue with hyaluronidase, presumably due to removal of hyaluronan bound to the HABP, and was abolished on treatment with hyaluronan hexasaccharide, presumably due to inhibition of HABP-antibody interaction. These results suggest that a hyaluronan receptor is involved in early cellular events in brain development.
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PMID:Monoclonal antibody to chick embryo hyaluronan-binding protein: changes in distribution of binding protein during early brain development. 171 84

Previously, we have shown that CD44 (the hyaluronan receptor) was involved in the degradation of hyaluronan. In the present study, we examined the distribution of CD44 and hyaluronan in the skin of embryonic and mature mice. During embryonic development, CD44 was prominently expressed by the condensed mesenchymal cells involved in the formation of the hair follicles, but was absent from the surrounding interstitial cells. The cells of the dermal condensation expressed CD44 throughout the development of the hair follicle; however, once the hair follicle reached maturity, the mesenchymal cells of the dermal papilla no longer expressed this molecule. In contrast to the above, the distribution of hyaluronan was reversed from that of CD44. Hyaluronan was widespread throughout the embryonic dermis, but was conspicuously absent from the regions of the dermal condensation. This arrangement persisted through the development of the hair follicle; however, in the mature hair follicle, hyaluronan reappeared in the dermal papilla. Thus, in the embryonic dermis, the expression of CD44 and hyaluronan were complementary to each other. However, in the adult skin, only minor changes were detected in the levels of CD44 and hyaluronan associated with the cells of the dermal condensation during the hair cycle. When organ cultures of embryonic mouse skin were treated with Streptomyces hyaluronidase, the interstitial mesenchymal cells became compacted, indicating that the removal of hyaluronan leads to the condensation of these cells. The results of this study are consistent with the hypothesis that the expression of CD44 by the inductive mesenchymal cells allows them to degrade hyaluronan in a localized region, leading to formation and maintenance of the dermal condensation.
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PMID:Hyaluronan is inversely correlated with the expression of CD44 in the dermal condensation of the embryonic hair follicle. 750 26

Several studies have suggested that chondrocytes must have the capacity to internalize and degrade extracellular hyaluronan. In the present study we show direct evidence that hyaluronan is, in fact, endocytosed by chondrocytes and that the endocytosis is mediated via cell surface CD44/hyaluronan receptors. Cultures of bovine articular chondrocytes as well as rat chondrosarcoma chondrocytes were incubated with either fluorescein- or 3H-labeled hyaluronan. Intense binding and accumulation of labeled hyaluronan was visualized by fluorescence microscopy or bright-field/dark-field microscopy following autoradiography. Cell surface hyaluronan was removed with either trypsin or Streptomyces hyaluronidase in order to distinguish and quantify intracellular endocytosed hyaluronan. Labeled hyaluronan was visualized within small discrete intracellular vesicles distributed throughout the cytoplasm. Binding and endocytosis of fluorescein- or 3H-labeled hyaluronan was totally blocked by the addition of excess unlabeled hyaluronan or hyaluronan hexasaccharides, competitive inhibitors of hyaluronan/hyaluronan receptor interactions. Binding and endocytosis was also blocked by the addition of anti-CD44 monoclonal antibodies. Characterization of endocytosed 3H-labeled hyaluronan demonstrated that a significant portion of the hyaluronan was degraded by both the bovine articular and rat chondrosarcoma chondrocytes. Interestingly, a higher proportion of bound hyaluronan was internalized by the bovine chondrocytes. Therefore, hyaluronan receptor-mediated endocytosis and degradation of hyaluronan may provide a critical link to the maintenance and homeostasis of cartilage tissue.
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PMID:Internalization of hyaluronan by chondrocytes occurs via receptor-mediated endocytosis. 750 84

Hyaluronan-binding sites were demonstrated on the cell surface of three malignant mesothelioma cell lines derived from human tumors using either [3H]hyaluronan or fluorescein-tagged hyaluronan. No hyaluronan-binding activity was observed on normal human mesothelial cells. The absence of hyaluronan receptors on normal human mesothelial cells was not due to a down-regulation by endogenously synthesized hyaluronan, since no binding sites appeared when the cells were cultured under conditions known to suppress hyaluronan synthesis (in starvation medium containing either hydrocortisone or n-butyrate) or to degrade endogenously synthesized hyaluronan (in the presence of Streptomyces or testicular hyaluronidase). The binding of [3H]hyaluronan on mesothelioma cells could be partially inhibited by prior incubation of the cells with trypsin, indicating that the hyaluronan-binding site is a protein. The binding sites on human malignant mesothelioma cells were shown to be saturable with about 54,000 hyaluronan molecules (M(r) 1.4 x 10(6)) bound per cell with a Kd of 0.3 x 10(-9) M. The binding was specific for hyaluronan inasmuch as a number of other macromolecules gave negligible inhibition of the binding. High molecular weight preparations of hyaluronan inhibited the binding more effectively than low molecular weight preparations; hyaluronan oligosaccharides down to a length of six monosaccharide units showed competing activity. The hyaluronan receptor appeared to be related to CD44 (a cell surface glycoprotein previously suggested to function as a hyaluronan receptor) since Hermes-1 monoclonal antibodies which inhibit the binding of hyaluronan to CD44 blocked a major part of the binding of hyaluronan to the mesothelioma cells. However, there was no strict correlation between the hyaluronan-binding activity on the mesothelioma cell lines tested and the levels of CD44 molecules on their cell surface, suggesting that only a subfraction of the CD44 molecules bound hyaluronan or that other hyaluronan-binding proteins also exist on those cells. The presence of hyaluronan receptors on mesothelioma cells, but not on their normal counterparts, may be of importance for the migration of the transformed cells in hyaluronan-enriched matrices and for their ability to form metastases.
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PMID:Hyaluronan receptors are expressed on human malignant mesothelioma cells but not on normal mesothelial cells. 751 23

Hyaluronan was localized in postimplantation mouse embryos using CD44, the principal hyaluronan receptor. The specificity of CD44 receptor-globulin labelling was confirmed using Streptomyces hyaluronidase, anti-chondroitin sulfate antibody, and other receptor globulins. Our major findings are summarized as follows: 1. Implantation of the blastocyst into the uterine wall triggers a rapid loss of hyaluronan from the extracellular matrix of decidual cells on the anti-mesometrial side of the uterus. 2. Hyaluronan appears early in development in the yolk cavity, and the basement membranes of primitive ectoderm and primitive endoderm. 3. During gastrulation, mesodermal cells enter a hyaluronan-rich environment, but lack a pericellular hyaluronan coat themselves. 4. In limb bud embryos, hyaluronan is present throughout the cranial mesenchyme, but is generally not present in the branchial bars, somites, or limb buds. 5. At mid-gestation, hyaluronan is present in the axial skeleton, craniofacial mesenchyme, endocardial cushions of the heart, smooth muscle of the gastrointestinal tract, and connective tissue throughout the body. The pattern of hyaluronan expression in the day 13 fetus is nearly identical to the published distribution of transforming growth factor beta (TGF beta), suggesting a close functional relationship between these molecules. Together, the results suggest that hyaluronan is involved in the formation of early mesoderm, differentiation of craniofacial mesenchyme, and morphogenesis of the axial skeleton.
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PMID:Localization of hyaluronan in mouse embryos during implantation, gastrulation and organogenesis. 769 85

Hyaluronan is a constituent of the extracellular matrix of connective tissue and is actively synthesized during wound healing and tissue repair to provide a framework for ingrowth of blood vessels and fibroblasts. Changes in the serum concentration of hyaluronan are associated with inflammatory and degenerative arthropathies such as rheumatoid arthritis. In addition, hyaluronan has been implicated as an important substrate for migration of adhesion of leukocytes during inflammation. A human hyaluronan synthase (HuHAS1) cDNA was isolated by a functional expression cloning approach. Transfection of CHO cells conferred hyaluronidase-sensitive adhesiveness of a mucosal T cell line via the lymphocyte hyaluronan receptor, CD44, as well as increased hyaluronan levels in the cultures of transfected cells. The HuHAS1 amino acid sequence shows considerable homology to the hasA gene product of Streptococcus pyogenes, a glycosaminoglycan synthetase from Xenopus laevis (DG42), and is the human homolog of a recently described murine hyaluronan synthase.
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PMID:Functional cloning of the cDNA for a human hyaluronan synthase. 879 44

The regulation of hyaluronan synthesis and shedding was analysed in human fibroblasts and in two melanoma cells that differed in the metastatic potential and proteolysis of the hyaluronan receptor CD44. Dissociation of nascent hyaluronan from plasma membranes isolated from fibroblasts by high salt concentrations led to activation of hyaluronan synthase. Hyaluronan synthesis was also enhanced in plasma membranes from fibroblasts that had been treated with hyaluronidase or trypsin. Hyaluronan oligosaccharides stimulated hyaluronan production in fibroblast cultures. These results indicated that nascent high-molecular-mass hyaluronan inhibited its own chain elongation, if it was retained in the vicinity of the synthase by cell-surface receptors. The results also indicated that increased hyaluronan synthesis and shedding correlated with proteolysis of CD44 on the melanoma cell lines, which has been observed by others.
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PMID:Synthesis and shedding of hyaluronan from plasma membranes of human fibroblasts and metastatic and non-metastatic melanoma cells. 1049 13

Hyaluronan synthesized in the epidermis has an exceptionally short half-life, indicative of its catabolism by epidermal keratinocytes. An intracellular pool of endogenously synthesized hyaluronan, from 1 to 20 fg/cell, inversely related to cell density, was observed in cultured rat epidermal keratinocytes. More than 80% of the intracellular hyaluronan was small (<90 kDa). Approximately 25% of newly synthesized hyaluronan was endocytosed by the keratinocytes and had a half-life of 2-3 h. A biotinylated aggrecan G(1) domain/link protein probe demonstrated hyaluronan in small vesicles of approximately 100 nm diameter close to the plasma membrane, and in large vesicles and multivesicular bodies up to 1300 nm diameter around the nucleus. Hyaluronan did not co-localize with markers of lysosomes. However, inhibition of lysosomal acidification with NH(4)Cl or chloroquine, or treating the cells with the hyaluronidase inhibitor apigenin increased intracellular hyaluronan staining, suggesting that it resided in prelysosomal endosomes. Competitive displacement of hyaluronan from surface receptors using hyaluronan decasaccharides, resulted in a rapid disappearance of this endosomal hyaluronan (t(12) approximately 5 min), indicating its transitory nature. The ultrastructure of the hyaluronan-containing vesicles, co-localization with marker proteins for different vesicle types, and application of specific uptake inhibitors demonstrated that the formation of hyaluronan-containing vesicles did not involve clathrin-coated pits or caveolae. Treatment of rat epidermal keratinocytes with the OX50 monoclonal antibody against the hyaluronan receptor CD44 increased endosomal hyaluronan. However, no CD44-hyaluronan co-localization was observed intracellularly unless endosomal trafficking was retarded by monensin, or cultivation at 20 degrees C, suggesting CD44 recycling. Rat epidermal keratinocytes thus internalize a large proportion of their newly synthesized hyaluronan into non-clathrin-coated endosomes in a receptor mediated way, and rapidly transport it to slower degradation in the endosomal/lysosomal system.
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PMID:Hyaluronan enters keratinocytes by a novel endocytic route for catabolism. 1145 52

Chondroitin sulphate, fibronectin, laminin and the hyaluronan receptor, CD44, were localized in ovine skin during follicle morphogenesis. Prior to initiation, chondroitin sulphate was detected in the mesenchyme adjacent to the dermal-epidermal junction and showed an approximately regular periodicity in staining intensity. With the appearance of follicle primordia, the more strongly stained regions of the matrix were associated with mesenchymal condensations. During later development and in the mature follicle, staining was localized to the matrices of cells of the dermal sheath and papilla. CD44 was also localized in the mesenchymal condensations at follicle initiation and, subsequently, in the dermal sheath. Fibronectin staining was confined to the mesenchyme prior to follicle formation and became associated with presumptive papilla and dermal sheath cells during follicle formation and maturation. Fibronectin antisera detected an approximately 220 kDa protein in western blots of adult and fetal skin. An additional band of 150 kDa was also observed prior to follicle initiation. In contrast, laminin was predominantly restricted to the basal laminae of developing and mature follicles. The aggregative behaviour of ovine papilla cells was examined in vitro. The number and size of aggregates were not affected by inclusion of chondroitin sulphate or fibronectin in the culture medium, but both increased in the presence of hyaluronidase. Chondroitinase had the opposite effect and beta-D-xyloside completely abolished aggregative behaviour. In conclusion, the appearance of certain matrix molecules may presage morphogenetic movements of cells at follicle initiation and regulate patterns of follicle distribution in skin during fetal life.
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PMID:Extracellular matrix molecules and follicle morphogenesis in ovine skin. 1172 Jan 31


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