Plc Gamma 1 Inhibition Combined With Inhibition Of Apoptosis And Necroptosis Increases Cartilage Matrix Synthesis In Il-1 Beta-Treated Rat Chondrocytes

Osteoarthritis (OA) is an age-related, chronic degenerative disease. With the increasing median age of the population, this disease has become an important public health problem. New, disease-modifying therapies are needed. A potential novel molecular target is phospholipase C gamma 1 (PLC gamma 1), a critical enzyme with important functions including calcium signaling regulation and cell proliferation. In rat chondrocytes treated with IL-1 beta (20 ng center dot mL(-1) for 36 h), inhibition of PLC gamma 1 with U73122 (2 mu m for 12 h) increased levels and expression of the cartilage matrix components Collagen2 and Aggrecan. This beneficial effect of PLC gamma 1 inhibition was counteracted by increased chondrocyte apoptosis and necroptosis, increased cell death, and increase levels of ROS, all potentially negative for OA. Combined treatment of IL-1 beta + U73122-treated chondrocytes with inhibitors of apoptosis (Z-VAD, 10 mu m) and necroptosis (Nec-1, 30 mu m) enhanced the increases in levels and expression of Collagen2 and Aggrecan, and prevented the increases in cell death and ROS levels. These results suggest that PLC gamma 1 inhibition may be a viable approach for an OA therapy, if combined with targeted inhibition of chondrocyte apoptosis and necroptosis.