title: Heparan sulphate proteoglycan in scleromyxedema promotes FGF-2 activity.
abstract: The cause of progressive dermal sclerosis, proliferation of fibroblasts, and collagen deposition in scleromyxedema is unknown. We analyzed the heparan sulphate proteoglycans (HSPG) in cutaneous nodules from a patient with scleromyxedema in order to ascertain their role in the binding of fibroblast growth factor (FGF) and promoting signaling complex assembly. Total heparan sulphate (HS) was detected with a monoclonal antibody to HSPG on paraffin sections. Binding of FGF to HS was assessed using FGF-2 followed by anti-FGF-2 antibody. The formation of HS-mediated signaling complex was studied using soluble FR1-AP, which contains the extracellular domain of FGF receptor-1 linked to alkaline phosphatase (AP) and monoclonal anti-AP-antibody. Anti FGF-2 and anti-AP antibodies were visualized using the DAKO Envision Plus system. The dermal nodule of scleromyxedema contained ample HS and these bound FGF-2 and FR1-AP. Specificity was confirmed by prior incubation with heparitinase (no staining) and omission of FGF-2 (no staining). Increased amounts of HSPG were present in the dermal nodules of scleromyxedema compared to adjacent normal dermis and these bound FGF-2, immobilized the soluble receptor protein FGFR-1 and, therefore, formed a ternary complex composed of HSPG, FGF-2 and FGFR-1 in vitro. Since this complex resembles the signaling complex formed on live cells, HSPG in the nodules of scleromyxedema are in a configuration that promotes FGF activity.
authors.affiliation: Department of Medicine, Division of Dermatology, University of Wisconsin Hospitals and Clinics Madison, Wisconsin, USA.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Warner
authors.forename: David A
authors.initials: DA
authors.lastname: Wrone
authors.forename: Eliot C
authors.initials: EC
authors.lastname: Williams
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Cripps
authors.forename: Christoph
authors.initials: C
authors.lastname: Mundhenke
authors.forename: Andreas
authors.initials: A
authors.lastname: Friedl
mesh_terms: D000328:Adult; D005148:Facial Dermatoses / Q000378:metabolism* / Q000473:pathology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017512:Lichenoid Eruptions / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009230:Myxedema / Q000378:metabolism* / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000473:pathology
chemical_list: D019812:Heparan Sulfate Proteoglycans; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; C496348:FGFR1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1