Adenoviral Gene Transfer of Interleukin-1 in Combination with Oncostatin M Induces Significant Joint Damage in a Murine Model

Abstract

Oncostatin M (OSM) is an interleukin (IL)-

Interleukin‐1 in combination with oncostatin M up‐regulates multiple genes in chondrocytes: Implications for cartilage destruction and repair

“…KC expression was primarily localized to the articular surfaces of the cartilage, concomitant with its role as a chemoattractant inducing the migration of neutrophils from the synovium toward the cartilage. IL-8 and ENA-78 are potent inducers of angiogenesis (32), which is a marked feature in our arthritis model (9,10). IL-8 also contributes to the pathologic changes observed in arthritis through p38 MAPK pathway activation (33), which can lead to hypertrophic differentiation, alteration in collagen subtype expression, and cartilage calcification.…”

“…IL-6, LIF, and OSM all belong to the glycoprotein-130-binding cytokine family (30). IL-6 and OSM are produced in RA synovium and can act synergistically with IL-1 and TNF␣ in the presence of their soluble receptors (7,31) to promote cartilage breakdown (6,9,10,21). An increase in the expression of OSM␤R may lead to prolonged activation of OSM-mediated signaling pathways (30), and one component that facilitates such signaling, Jak-2 kinase, was also notably induced.…”

“…Realtime polymerase chain reaction (PCR) Master Mix reagents were obtained from Roche (Lewes, UK). All other chemicals were commercially available and of analytic grade, as described previously (7,10).…”

“…An established model of inflammatory arthritis was used, in which replication-deficient adenovirus was engineered to express murine IL-1 and murine OSM at 1 ϫ 10 6 plaque-forming units/joint/vector, as described previously (9,10). At 7 days after injection of the adenovirus vectors, joints were dissected, fixed overnight in 7% formaldehyde in PBS (pH 7.4), decalcified in 10% EDTA in PBS for 10 days, and wax-embedded.…”

“…Furthermore, we have also demonstrated that this combination induces a marked inflammatory arthritis in vivo, which is characterized by pronounced synovial hyperplasia, increased inflammatory infiltrate, marked cartilage and bone erosions, and elevated MMP expression (9,10). In IL-1 plus OSM-treated human chondrocytes, the most striking observation is a pronounced induction of MMP-1 (10,11), as well as other MMPs, ADAM proteinases, and ADAMTS proteinases (11). Traditionally, inflammation and destruction of bone and cartilage have been linked, although this may not be the case (12).…”