heparitin-sulfate and Psoriasis

Heparan sulfate proteoglycans (HSPGs) are components of the basement membrane (BM) of various tissues. They consist of a core protein and negatively charged glycosaminoglycan side chains: the heparan sulfate (HS) moieties. In psoriasis, uninvolved skin of psoriasis patients and in normal skin, the distribution of HSPGs was studied immunohistochemically by means of three different monoclonal antibodies: JM-72, directed against the HSPG-core protein, JM-13 against the sulfated domains of HS and JM-403 against the unmodified/low sulfated parts of HS. In psoriasis JM-13 staining was consistently absent in the tips of the dermal papillae, whereas JM-13 showed a continuous staining in the BM of uninvolved and normal skin. JM-403 staining was present in BM of all specimens. In addition, a honeycomb-like staining was found in epidermis of normal skin and to a lesser extent in uninvolved skin, due to binding with plasma membrane-associated HS. In psoriasis this JM-403 staining of the epidermis was invariably absent. JM-72 showed a continuous staining of BM in all biopsies. In conclusion, normal human skin and involved psoriatic skin show clear differences in expression of HS. These data may provide insight into the role of HSPGs in psoriasis, which remains further to be elucidated.

Topics: Adult; Aged; Antibodies, Monoclonal; Basement Membrane; Culture Techniques; Female; Heparitin Sulfate; Humans; Immunohistochemistry; Male; Middle Aged; Psoriasis; Tissue Distribution

Amphiregulin and transforming growth factor-alpha, agonists for the epidermal growth factor receptor, are the major autocrine growth factors for cultured keratinocytes, and their substantial overexpression in psoriatic lesions suggests that they are crucial to the basal hyperplasia that characterizes psoriasis. Amphiregulin binds to heparin and related highly sulfated polysaccharides, and exogenous heparin blocks its growth factor activity, rationalizing previous reports that psoriasis responds to heparin therapy. Differentiating keratinocytes produce increased amounts of protein-bound as well as free-chain heparan sulfates, which may function physiologically as amphiregulin antagonists. By promoting keratinocyte synthesis of these heparan sulfates, glucosamine administration may inhibit amphiregulin function and thus provide therapeutic benefit in psoriasis. Concurrent ingestion of fish oil, by impeding the excessive activation of protein kinase C, may decrease keratinocyte production of amphiregulin and other autocrine growth factors, thus complementing the postulated benefits of glucosamine.

Topics: Amphiregulin; EGF Family of Proteins; ErbB Receptors; Fish Oils; Glucosamine; Glycoproteins; Growth Substances; Heparitin Sulfate; Humans; Intercellular Signaling Peptides and Proteins; Models, Biological; Psoriasis; Transforming Growth Factor alpha

Application of leukotriene B4 (LTB4) to normal human skin induces changes similar to those found in psoriatic skin, and it has proved to be a useful model for studying the pathogenesis and treatment of psoriasis. We studied the expression patterns of molecules that have recently been shown to be altered in lesional psoriatic skin, including the extracellular matrix protein tenascin (TN) and the basement membrane and cell surface-associated heparan sulfate proteoglycans (HSPGs). During 72-h the expression of these markers was studied immunohistochemically and the expression of TN was correlated with epidermal proliferation and influx of inflammatory cells. Following the peak influx of polymorphonuclear leukocytes, a marked increase in TN expression was noted in the papillary dermis 72 h after LTB4 application. The expression patterns of basal membrane-associated epitopes of HSPG remained unaltered, whereas the expression of cell surface-associated HSPG disappeared 72 h after LTB4 application. A significant correlation was found between dermal TN expression and epidermal hyperproliferation, and between TN expression and the presence of dermal T cells. These findings indicate that the model of LTB4-induced acute cutaneous inflammation displays many characteristics of early psoriatic lesions and could serve as a model to study some of the cell biological changes in this disease.

Topics: Administration, Cutaneous; Adult; Cell Division; Dermatitis, Irritant; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Immunohistochemistry; Inflammation; Leukotriene B4; Male; Models, Biological; Proteoglycans; Psoriasis; Skin; Tenascin

Glycosaminoglycan-modified isoforms of CD44 have been implicated in growth factor presentation at sites of inflammation. In the present study we show that COS cell transfectants expressing CD44 isoforms containing the alternatively spliced exon V3 are modified with heparan sulfate (HS). Binding studies with three HS-binding growth factors, basic-fibroblast growth factor (b-FGF), heparin binding-epidermal growth factor (HB-EGF), and amphiregulin, showed that the HS-modified CD44 isoforms are able to bind to b-FGF and HB-EGF, but not AR. b-FGF and HB-EGF binding to HS-modified CD44 was eliminated by pretreating the protein with heparitinase or by blocking with free heparin. HS-modified CD44 immunoprecipitated from keratinocytes, which express a CD44 isoform containing V3, also bound to b-FGF. We examined whether HS-modified CD44 isoforms were expressed by activated endothelial cells where they might present HS-binding growth factors to leukocytes during an inflammatory response. PCR and antibody-binding studies showed that activated cultured endothelial cells only express the CD44H isoform which does not contain any of the variably spliced exons including V3. Immunohistological studies with antibodies directed to CD44 extracellular domains encoded by the variably spliced exons showed that vascular endothelial cells in inflamed skin tissue sections do not express CD44 spliced variants. Keratinocytes, monocytes, and dendritic cells in the same specimens were found to express variably spliced CD44. 35SO4(-2)-labeling experiments demonstrated that activated cultured endothelial cells do not express detectable levels of chondroitin sulfate or HS-modified CD44. Our results suggest that one of the functions of CD44 isoforms expressing V3 is to bind and present a subset of HS-binding proteins. Furthermore, it is probable that HS-modified CD44 is involved in the presentation of HS-binding proteins by keratinocytes in inflamed skin. However, our data suggests that CD44 is not likely to be the proteoglycan principally involved in presenting HS-binding growth factors to leukocytes on the vascular cell wall.

Topics: Alternative Splicing; Antibodies, Monoclonal; Base Sequence; Carrier Proteins; Dermatitis, Allergic Contact; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Exons; Fibroblast Growth Factor 2; Flow Cytometry; Genetic Variation; Growth Substances; Heparin-binding EGF-like Growth Factor; Heparitin Sulfate; Hyaluronan Receptors; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Ligands; Molecular Sequence Data; Polymerase Chain Reaction; Psoriasis; Receptors, Cell Surface; Receptors, Lymphocyte Homing; Recombinant Fusion Proteins; RNA, Messenger

Topics: Epidermis; Glycosaminoglycans; Heparitin Sulfate; Humans; Psoriasis; Receptors, Fibronectin; Receptors, Immunologic; Skin

Using a material consisting of related dermal specimens and 24-h urine samples from 17 psoriatics and 20 non-psoriatics it has been shown for the first time that the excretion of dermatan sulphate and a fraction of chondroitinase ABC resistant GAG ('heparan sulphate') are positively associated with the tissue content of the analytically identical glycosaminoglycans in dermis. The excretion of chondroitin 4/6 sulphate, total hydroxyproline and a peptide-bound fraction of this does not, however, mirror the tissue content of the corresponding constituents in dermis. There was no difference in the type of association between tissue and urine measurements in psoriatics and non-psoriatics. The results were analysed using multiple regression to avoid the unwanted effect of diverse concomitant variables (6 variables).

Topics: Chondroitin Lyases; Chondroitin Sulfates; Circadian Rhythm; Dermatan Sulfate; Glycosaminoglycans; Heparitin Sulfate; Humans; Hydroxyproline; Psoriasis; Skin; Uronic Acids

Primary irritant dermatitis includes an inflammatory process of connective tissue which is of general interest. For the first time this process has been characterised biochemically in humans by following the dermal changes in the concentration of hydroxyproline and four glycosaminoglycans. In healthy individuals (n = 7) and in psoriatics (n = 8) the changes were rather similar. Only dermatan sulphate showed a tendency towards an abnormal response in the psoriatics. In both groups the deviations from the pre-irritant condition clearly distinguished the response of irritant dermatitis from that of the wound healing process: (1) the concentration of hyaluronic acid decreased by the third day and remained so until by the sixth day, (2) after a decrease on the third day the concentration of dermatan sulphate returned to the initial value by the sixth day, (3 and 4) the concentration of chondroitin 4/6-sulphate and heparan sulphate increased continuously from the third to the sixth day, and (5) the concentration of hydroxyproline remained constant throughout the period of investigation.

Topics: Adult; Aged; Benzalkonium Compounds; Chondroitin Sulfates; Dermatan Sulfate; Dermatitis, Contact; Female; Glycosaminoglycans; Heparitin Sulfate; Humans; Hyaluronic Acid; Hydroxyproline; Male; Middle Aged; Psoriasis; Skin

The investigation included 17 psoriatics and 19 healthy controls. The content of sulphate per disaccharide unit (sulphate/uronic acid ratio) was measured in the sulphated glycosaminoglycans (GAGs) isolated from urine and dermal biopsies of the gluteal region. Biopsies were taken from both involved and uninvolved skin of the psoriatics. Perfectly normal sulphate/uronic acid ratios were found in the involved and uninvolved skin as well as in the urine of the psoriatics. A close and positive correlation between the sulphate/uronic acid ratio of the sulphated GAGs in the affected and unaffected skin of the psoriatics was discovered. The results are discussed in relation to earlier findings on the same specimens which shows that the concentration of sulphated GAGs in the psoriatic lesions is increased (28%) as is the urinary excretion of sulphated GAG in the same patients (62%).

Topics: Adult; Aged; Chondroitin Sulfates; Dermatan Sulfate; Female; Glycosaminoglycans; Heparitin Sulfate; Humans; Hyaluronic Acid; Male; Middle Aged; Psoriasis; Skin; Sulfates; Uronic Acids

The investigation included 15 psoriatic patients and 14 healthy controls. By using a simple method based on susceptibility to chondroitinases the excretion of dermatan sulphate, chondroitin-4/6-sulphate and heparan sulphate in the psoriatics was found to be increased with 104, 62 and 47% from uronic acid mean excretions of 1.97, 6.37 and 5.10 mumol/24 h, respectively. The excretion of hydroxyproline was not increased. In both groups the excretion of hyaluronic acid was insignificant. The absolute increase in the excretion of a major skin component like dermatan sulphate was exceeded by the excretion of chondroitin-4/6-sulphate and heparan sulphate which are both small components of skin. This indicates a comparatively high turnover of those two fractions in psoriatic lesions. The fact, that only the excretion of dermatan sulphate correlated with the fraction of skin surface involved in the psoriatic disease, indicated an important origin of this fraction, as well as the possibility of dermatan sulphate as a means of following dermal metabolism.

Topics: Adult; Aged; Chondroitin; Chondroitin Sulfates; Chondroitinases and Chondroitin Lyases; Dermatan Sulfate; Electrophoresis, Cellulose Acetate; Female; Heparitin Sulfate; Humans; Hyaluronic Acid; Hydroxyproline; Male; Middle Aged; Psoriasis

Topics: Acute Disease; Chromatography, DEAE-Cellulose; Chromatography, Paper; Dermatitis, Exfoliative; Electrophoresis, Paper; Galactosamine; Galactose; Glucosamine; Glycosaminoglycans; Heparitin Sulfate; Humans; Hyaluronoglucosaminidase; Male; Middle Aged; Psoriasis; Quaternary Ammonium Compounds; Skin; Sulfuric Acids; Testis; Time Factors; Ultrafiltration; Uronic Acids