Oncostatin M induces angiogenesis and cartilage degradation in rheumatoid arthritis synovial tissue and human cartilage cocultures

Arthritis Rheum. 2006 Oct;54(10):3152-62. doi: 10.1002/art.22161.


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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arthritis, Rheumatoid / pathology*
  • Cartilage / metabolism
  • Cartilage / pathology*
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Coculture Techniques
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism
  • Extracellular Matrix / pathology
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Gene Expression Regulation
  • Humans
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism
  • Interleukin-1beta / pharmacology
  • Matrix Metalloproteinase 1 / genetics
  • Matrix Metalloproteinase 1 / metabolism
  • Neovascularization, Pathologic / pathology*
  • Oncostatin M / physiology*
  • Synovial Membrane / metabolism
  • Synovial Membrane / pathology*
  • Tissue Inhibitor of Metalloproteinase-1 / genetics
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Vascular Cell Adhesion Molecule-1 / genetics
  • Vascular Cell Adhesion Molecule-1 / metabolism
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism


  • Interleukin-1beta
  • Tissue Inhibitor of Metalloproteinase-1
  • Vascular Cell Adhesion Molecule-1
  • Vascular Endothelial Growth Factor A
  • Oncostatin M
  • Intercellular Adhesion Molecule-1
  • Matrix Metalloproteinase 1