U50 488H KOR agonist reduces cartilage degradation, chondrocyte hypertrophy and bone loss in osteoarthritis.

Osteoarthritis is a chronic joint disease-causing significant pain and discomfort especially in the aging population. It is characterized by inflammation, extracellular matrix degradation, chondrocyte apoptosis, hypertrophy and subchondral bone degeneration. In this study, we explored the disease modifying activity of Kappa Opioid Receptor (KOR) agonist U50 488H in in-vitro and in-vivo model of osteoarthritis. U50 488H reduced the production of pro-inflammatory cytokines, lowered reactive oxygen species (ROS) generation and inhibited the expression of hypertrophic and catabolic factors induced by IL-1β in rat articular chondrocytes. Additionally, the intra articular injection of U50 488H slowed the progression of osteoarthritis in anterior cruciate ligament transected (ACLT) rat model. Histological findings revealed that U50 488H preserved the proteoglycan content, cartilage thickness and cartilage integrity. Furthermore, subchondral bone analysis by micro-CT demonstrated that KOR agonist protected the bone microarchitecture. In conclusion, these findings suggest that KOR signalling has both chondroprotective and osteoprotective effects in osteoarthritic condition.