Oncostatin M in rheumatoid arthritis: a key cytokine acts synergistically with other proinflammatory cytokines to promote human cartilage loss

Introduction

Oncostatin M (OSM), an IL-6 type cytokine, is raised in the rheumatoid arthritis (RA) joint and correlates with markers of inflammation and cartilage destruction. This study explores the mechanistic role of OSM in cell adhesion, angiogenesis and matrix degradation.

Methods

Microvascular endothelial cells (EC), primary RA synovial fibroblasts (SFC), synovial explant culture and RASFC/normal cartilage co-cultures were stimulated with OSM (20 ng/ml) ± IL-1 (5 ng/ml). Cell proliferation, cell adhesion molecules expression, tubule formation, cell migration and matrix degradation were assessed by proliferation, flow cytometry, matrigel angiogenesis and ELISA assays.

Results

OSM stimulated EC/RASFC (basal = 0.9/0.56 to 1.56/1.94; P < 0.05, day 4) alone but demonstrated a synergistic effect in the presence of IL-1 (P < 0.01). OSM and IL-1 increased intercellular adhesion molecule expression, with no effect on vascular cell adhesion molecule or platelet endothelial cell adhesion molecule. OSM had an additive effect with IL-1 on intercellular adhesion molecule expression (P < 0.05). OSM increased EC tubule formation (basal = 20 ± 1.5 to 47 ± 3.7; mean ± standard error, P < 0.01), and increased EC migration (basal = 1.265 ± 0.115 to 1.67 ± 0.187; P < 0.05). OSM synergistically increased TIMP-1 production in EC, SFC and synovial explants in the presence of IL-1, with no effect on αvβ3 or urokinase (-type plasminogen activator) receptor expression. OSM and IL-1 stimulated MMP-1 and MMP-13 expression in cartilage and SFC alone (P < 0.05) but had a significant threefold synergistic induction when cultured together (P < 0.01). Cartilage sections stained with safranin-O demonstrated almost complete depletion of proteoglycan expression in RASFC/cartilage co-cultures following 4 weeks incubation with IL-1/OSM. This was reflected in the supernatants where IL-1 and OSM together synergistically increased GAG release from a basal level of 3.5–9.1 (μg GAG/mg cartilage weight) compared with either IL-1 or OSM alone.

Conclusion

OSM plays a critical role in RASFC activation and cartilage invasion, also promoting angiogenesis. Its ability to act synergistically with other proinflammatory cytokines such as IL-1 further supports a key role for OSM in RA.