title: Gorham-Stout syndrome: a monocyte-mediated cytokine propelled disease.
abstract: We studied the biological features and the immunophenotype of a cell culture established from the lesion of soft tissues of a woman affected by Gorham-Stout syndrome. We found that these cells belonged to a monocytic lineage with some characteristics of immature osteoclasts and were able to release large amounts of osteoclastogenic and angiogenic molecules that may contribute to disease progression.
  
  
  BACKGROUND
  Gorham-Stout syndrome is a rare disease characterized by osteolysis and proliferation of vascular or lymphatic vessels, with a severe outcome. Its etiology and the identification of the cell types involved are completely unknown.
  
  
  METHODS
  A cell culture from a lesion of soft tissues was established, and its behavior in vitro and in immunodeficient mice was studied. We analyzed (1) the cell phenotype by flow cytometry; (2) the adhesive and migratory properties on different substrates; (3) the ability to differentiate into mature osteoclasts; (4) the production of osteclastogenic and angiogenic molecules; (5) the in vivo angiogenic activity of the cells subcutaneously implanted in mouse in a Matrigel plug; and (6) the ability to recapitulate the disease when transplanted in nude mice.
  
  
  CONCLUSIONS
  The established culture consisted of a morphologically homogeneous cell population belonging to a monocytic lineage having some features of an osteoclast-like cell type. Cells had an invasive phenotype, were angiogenic, and produced osteoclastogenic (IL-6, TGF-beta1, IL-1beta) and angiogenic (vascular endothelial growth factor-A [VEGF-A], CXCL-8) molecules when challenged with inflammatory cytokines. Immunodeficient mice injected with these cells did not show any bone lesions or vascular alteration, but had high amounts of circulating human IL-6 and VEGF-A. Cells isolated from a cutaneous lymphangiomatosis did not show any of these findings. These data suggest that cells of monocyte-macrophage lineage play an essential role in the pathogenesis of Gorham-Stout disease, whose progression is propelled by cytokine circuits that accelerate angiogenesis and osteoclastogenesis.
authors.affiliation: Istituto di Anatomia Umana Normale, Università di Bari, Bari, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Colucci
authors.forename: Giulia
authors.initials: G
authors.lastname: Taraboletti
authors.forename: Luca
authors.initials: L
authors.lastname: Primo
authors.forename: Andrea
authors.initials: A
authors.lastname: Viale
authors.forename: Cristina
authors.initials: C
authors.lastname: Roca
authors.forename: Donatella
authors.initials: D
authors.lastname: Valdembri
authors.forename: Massimo
authors.initials: M
authors.lastname: Geuna
authors.forename: Marco
authors.initials: M
authors.lastname: Pagano
authors.forename: Maria
authors.initials: M
authors.lastname: Grano
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Pogrel
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.forename: Nicholas N
authors.initials: NN
authors.lastname: Athanasou
authors.forename: Alberto
authors.initials: A
authors.lastname: Mantovani
authors.forename: Alberta
authors.initials: A
authors.lastname: Zallone
authors.forename: Federico
authors.initials: F
authors.lastname: Bussolino
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000032:analysis; D001842:Bone and Bones / Q000276:immunology / Q000473:pathology; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D009000:Monocytes / Q000276:immunology*; D009389:Neovascularization, Pathologic; D010010:Osteoclasts / Q000166:cytology*; D010015:Osteolysis, Essential / Q000276:immunology* / Q000473:pathology*; D013577:Syndrome
chemical_list: D000954:Antigens, Surface; D016207:Cytokines