A Three-Dimensionally Engineered Biomimetic Cartilaginous Tissue Model for Osteoarthritic Drug Evaluation

Osteoarthritis (OA) is primarily characterized by focal cartilage destruction and synovitis. Presently, the pathogenesis of OA remains unclear, and an effective treatment methodology is an unmet need. To this end, a plethora of animal models and monolayer models have been developed, but they are faced with the limitation of high cost and inability to recapitulate a pure hyaline cartilaginous phenotype, which is important in studying the efficacy of therapeutic agents. We have previously developed a living hyaline cartilage graft (LhCG) that accurately presented a pure hyaline cartilage phenotype. Here, through the coculture of lipopolysaccharide (LPS)-activated macrophages with LhCG, we hypothesized that an accurate OA disease model may be developed. Subsequently, this model was evaluated for its accuracy for in vitro drug testing. Results indicated that chondrocyte proliferation and apoptosis were increased in the disease model. Additionally, extracellular matrix (ECM) synthesis increased as indicated by the increased anabolic gene expression levels, such as collagen type II and aggrecan. Up-regulation of matrix metalloproteinase-1 (MMP-1) and MMP-3 genes suggested increased degradative activity, while chondrocytic hypertrophic differentiation was observed. Furthermore, extensive degradation of collagen type II and glycosaminoglycans (GAGs) were also observed. The results of celecoxib treatment on our model showed inhibition of nitric oxide (NO) and prostaglandin E2 (PGE2) production, as well as down-regulation of MMP-1 and MMP-3 expression. Taken together, the results suggested that this coculture model was able to sufficiently mimic the native, diseased OA cartilage, while drug testing results confirmed its suitability as an in vitro model for predicting native cartilage response to drug treatment.