15-Deoxy-Δ^12,14-prostaglandin J₂ induces apoptosis via JNK-mediated mitochondrial pathway in osteoblastic cells

The cyclopentenone prostaglandin 15-deoxy-Δ^12,14-prostaglandin J₂ (15d-PGJ₂) induces apoptosis in various cell types. However, the underlying mechanism of 15d-PGJ₂-induced apoptosis is not fully understood. The present study was undertaken to determine the molecular mechanism by which 15d-PGJ₂ induces apoptosis in MC3T3-E1 mouse osteoblastic cells. 15d-PGJ₂ caused a concentration- and time-dependent apoptotic cell death. 15d-PGJ₂ induced a transient activation of ERK1/2 and sustained activation of JNK. 15d-PGJ₂-induced cell death was prevented by the JNK inhibitor SP6001, but not by inhibitors of ERK1/2 and p38. JNK activation by 15d-PGJ₂ was blocked by antioxidants N-acetylcysteine (NAC) and GSH. 15d-PGJ₂ caused ROS generation and 15d-PGJ₂-induced cell death was prevented by antioxidants, suggesting involvement of ROS generation in 15d-PGJ₂-induced cell death. 15d-PGJ₂ triggered the mitochondrial apoptotic pathway indicated by enhanced Bax expression, loss of mitochondrial membrane potential, cytochrome c release, and caspase-3 activation. The JNK inhibitor blocked these events induced by 15d-PGJ₂. Taken together, these results suggest that the 15d-PGJ₂ induces cell death through the mitochondrial apoptotic pathway dependent of ROS and JNK activation in osteoblastic cells.