Osteoarthritis (OA) affects the entire joint including tissues like synovium, cartilage, meniscus and bone. Abnormal mechanical stresses (from injury or aging) produce elevated levels of inflammatory cytokines that degrade joint tissues and cause excessive neovascularization and angiogenesis. It is critical to develop effective early interventions that target both synovium, the primary initiator and source of inflammation mediators, as well as tissues like cartilage, that are at risk of irreversible proteolytic degradation.

Currently employed in vitro models, however, mostly use cartilage monocultures. Here we develop a co-culture model containing cartilage, synovium and meniscus to investigate biological and transport crosstalk between multiple joint tissues. Our data showed that co-culturing cartilage with synovium in the presence of inflammatory cytokine IL-1α, resulted in significantly higher chondrocyte death and reduced cell metabolism. Surprisingly, presence of synovium in co-culture helped significantly reduce chondrocyte nitrite production, suggesting release of anti-inflammatory factor by the synovium upon cytokine challenge. Presence of meniscus in co-culture did not present as significant of an effect as synovium did. However, culturing three tissues together increased cell death in cartilage by 3 weeks. These results confirm that significant biological crosstalk exists between various tissues. Thus co-culture systems should be preferred over monocultures to model the multiple complex pathways underlying OA.

It is widely accepted that OA is a disease of the entire joint and that no single compound will be sufficient to treat every aspect of OA, thus requiring a combination of therapeutics. We therefore, investigated the role of receptor antagonist IL-1Ra, growth factor IGF-1 and chondrocyte differentiator Kartogenin (KGN) in suppressing IL-1α induced catabolic activity using monoculture or co-culture models. Drugs were introduced in either a single (mimicking one-time intraarticular injection) or continuous (mimicking multiple injections) dose regimen. Our results showed that single drug-dose was insufficient and that continuous dose, which helped maintain constant drug concentration over the entire culture period, is necessary to elicit an effective therapeutic response. This highlights the need for developing sustained and targeted drug-delivery systems for OA treatment. Future work will focus on designing strategies for co-targeting multiple tissues with multiple drugs to provide a combination OA therapy