201 - Butein: A Plant Derived Small Molecule Activates Autophagy and Suppresses IL-1β Induced Oxidative Stress, Mitochondrial Dysfunction and Inflammatory Response in Human Chondrocytes

Abstract

Osteoarthritis (OA) is the most common joint disease worldwide and is characterized by pain and stiffness due to the progressive loss of articular cartilage. There is increasing evidence that support a role of high levels of oxidative stress, increased mitochondrial dysfunction, inflammation and decline in autophagy in the pathogenesis of OA. Currently there is no disease modifying drug available for the treatment of OA. Autophagy is a cellular defense mechanism against stress-induced accumulation of protein aggregates and dysfunctional subcellular organelles. Here, we studied the effect of a plant derived small molecule, Butein, on human chondrocytes and cartilage explants (isolated from donors with and without known history of OA) against IL-1β induced oxidative stress, mitochondrial dysfunction and expression of inflammatory mediators (Cyclooxygenase 2 (COX-2), inducible Nitric Oxide Synthase (iNOS) and interleukin-6 (IL-6) in vitro . Butein blocked the IL-1β induced disruption of mitochondrial membrane potential and mitochondrial dysfunction and suppressed the generation of total and mitochondrial ROS and RNS levels in normal and OA chondrocytes. Additionally, IL-1β induced expression of iNOS, COX-2 and IL-6 was also inhibited by Butein in both normal and OA chondrocytes and cartilage explants. Butein activated AMPKα and inhibited mTOR activity to activate autophagy in human chondrocytes as evidenced by the increased levels of LC3-II, decreased levels of p62/SQSTM1 and increased numbers of autophagosomes. Activation of autophagy was critical to the observed chondroprotective effects as inhibition of autophagy abrogated the protective effects of Butein. These results suggest that Butein may be developed as a therapeutic agent for the prevention and or treatment of OA.