title: Oncostatin M induces angiogenesis and cartilage degradation in rheumatoid arthritis synovial tissue and human cartilage cocultures.
abstract: OBJECTIVE
  To investigate the role of oncostatin M (OSM) in cell adhesion, angiogenesis, and matrix degradation in rheumatoid arthritis (RA) synovial tissue and normal human cartilage.
  
  
  METHODS
  Human dermal microvascular endothelial cell (HDMEC) and RA synovial fibroblast (RASF) proliferation and intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) expression were assessed by a bromodeoxyuridine proliferation assay and flow cytometry. HDMEC tubule formation and migration were assessed by Matrigel culture and migration assay. Production of matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinases 1 (TIMP-1) in RA synovial explants, and proteoglycan/glycosaminoglycan (GAG) release, vascular endothelial growth factor (VEGF), and angiopoietin 2 production from RASF/normal cartilage cocultures were assessed by enzyme-linked immunosorbent assay and immunohistology.
  
  
  RESULTS
  HDMEC/RASF proliferation was induced by OSM and interleukin-1beta (IL-1beta), alone and in combination. OSM enhanced cell surface expression of ICAM-1, but not VCAM-1, on endothelial cells and RASFs. OSM increased endothelial cell tubule formation and migration. In RA synovial explants, OSM induced production of MMP-1 and TIMP-1. When OSM was combined with IL-1beta, however, the MMP-1:TIMP-1 ratio was significantly increased. OSM potentiated IL-1beta-induced MMP-1 and MMP-13 expression in normal human cartilage/RASF cocultures, resulting in a significant increase in the MMP:TIMP ratio. In OSM/IL-1beta- stimulated cocultures, cartilage sections demonstrated significant proteoglycan depletion that was paralleled by a significant increase in GAG release in supernatants. Finally, compared with either cytokine alone, the combination of OSM and IL-1beta significantly induced VEGF production in RASF/cartilage cocultures.
  
  
  CONCLUSIONS
  These data suggest that OSM promotes angiogenesis and endothelial cell migration and potentiates the effects of IL-1beta in promoting extracellular matrix turnover and human cartilage degradation. Furthermore, the induction of VEGF in cocultures supports the hypothesis of a link between angiogenesis and cartilage degradation.
authors.affiliation: St. Vincent's University Hospital and the Conway Institute of Biomolecular and Biomedical Research, Dublin, Ireland.
authors.forename: Ursula
authors.initials: U
authors.lastname: Fearon
authors.forename: Ronan
authors.initials: R
authors.lastname: Mullan
authors.forename: Trevor
authors.initials: T
authors.lastname: Markham
authors.forename: Mary
authors.initials: M
authors.lastname: Connolly
authors.forename: Shane
authors.initials: S
authors.lastname: Sullivan
authors.forename: A Robin
authors.initials: AR
authors.lastname: Poole
authors.forename: Oliver
authors.initials: O
authors.lastname: FitzGerald
authors.forename: Barry
authors.initials: B
authors.lastname: Bresnihan
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Veale
mesh_terms: D001172:Arthritis, Rheumatoid / Q000473:pathology*; D002356:Cartilage / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005109:Extracellular Matrix / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000473:pathology*; D053683:Oncostatin M / Q000502:physiology*; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D019715:Tissue Inhibitor of Metalloproteinase-1; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D053683:Oncostatin M; D018799:Intercellular Adhesion Molecule-1; D020781:Matrix Metalloproteinase 1