IN VITRO AND EX VIVO OSTEOARTHRITIS MODELS AND THERAPIES

Osteoarthritis (OA) is a chronic disease affecting more and more people worldwide as the result of increased life expectancy. It is characterized by inflammation of the joint, pain and degradation of the cartilage. Current treatments consist of anti-inflammatory and analgesic drugs, with limited efficacy and inability to prevent cartilage degradation. To facilitate preclinical testing of emerging therapies, we established various in vitro and ex vivo OA models with joint tissue or 3D scaffolds culture. A low O 2 work station and mechanical loading bioreactor are used to simulate the in vivo condition of articulating joints for investigation of the efficacy and mechanism of OA therapeutics under physiological microenvironment. We have established an ex vivo OA model with human osteochondral explants harvested from femoral head with an 8-mm trephine. Simultaneous application of IL-1b and TNFa could induce cartilage matrix degradation and release of inflammatory mediators, which mimics the tissue changes during OA progression [1]. Since synovium tissue plays an important role in inflammation regulation during OA progression, we further established an osteochondral explant synovium tissue co-culture OA model [2]. Healthy cartilage had no adverse effects on synovium tissue. Inflamed cartilage in the coculture system could aggravate inflammatory and catabolic responses in the synovium. Using these models we investigated the effect of 5-Aminosalicylic acid (5-ASA) for OA treatment [3]. Currently, we are investigating the effect of Glucagon-like Peptide-1 Receptor Agonist (GLP-1RA) as disease modifying therapy for OA treatment. Existing clinical studies have only tested systemically administered GLP-1RA drugs for OA treatment. We hypothesize that intra-articular administration of the drug could ameliorate OA progression through functioning on the GLP1 receptors expressed by multiple tissues in the articular joint. Efficacy of the GLP-1RA liraglutide was tested in an in vitro 3D OA model formed with human chondrocytes. Results showed that liraglutide has anti-inflammatory and anabolic effects on IL-1β-induced human chondrocyte pellets cultured in vitro . IL-1β induces inflammatory responses in human chondrocytes cultured in scaffolds under mechanical loading condition. Liraglutide showed donor-dependent and dose-dependent anti-inflammatory and anabolic effects on human chondrocytes cultured in scaffolds under mechanical loading condition.