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

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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‐1β (IL‐1β), 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‐1β, however, the MMP‐1:TIMP‐1 ratio was significantly increased. OSM potentiated IL‐1β–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‐1β– 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‐1β 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‐1β 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.

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