UC San Diego

Osteoarthritis (OA) is a chronic disease characterized by a degradation of the articular cartilage, increases in catabolic responses, and inflammation. Osteoarthritis is a leading cause of disability the world, and an enormously expensive health problem. Biomechanical injury or excess joint use is a known risk factor for the development of osteoarthritis. To identify chondrocyte abnormalities that provide a basis upon which OA is accelerated we studied the unfolded protein response (UPR), a fundamental means by which cells normally resolve stress. The UPR restores equilibrium to the ER via a reprogrammed proteome rich in chaperones and protein folding catalyst. Three UPR signaling cascades are triggered by dissociation of ER membrane proteins from the chaperone GRP78, which normally dampens the UPR, and limits apoptosis. Each UPR specific cascade promotes terminal expression of CHOP, with unsuccessful resolution of the UPR promoting oxidative stress, inflammation, and apoptosis. Chondrocytes stimulated with sub-lethal cyclic compressive stress demonstrated rapid increase in the UPR over 1-7 days in both as indicated by increased expression of both GRP78 and CHOP. However, our lab has previously shown that AMP- activated protein kinase (AMPK) a regulator of energy homeostasis and cellular inflammatory cytokines. We therefore stimulated chondrocytes with pharmacological activators of AMPK and tested the effects of AMPK activators on UPR expression and chondrocyte catabolic activity. Catabolic responses, and activation of the UPR were significantly decreased post injury. Targeted activation of AMPK may have the potential to protect articular cartilage from degradation caused by biomechanical injury, and slow the progression of OA