Reciprocal Role of ERK and NF-(kappa)B Pathways in Survival and Activation of Osteoclasts

To examine the role of mitogen-activated protein kinase and nuclear factor kappa B (NF-(kappa)B) pathways on osteoclast survival and activation, we constructed adenovirus vectors carrying various mutants of signaling molecules: dominant negative Ras (Ras(super DN)), constitutively active MEK1 (MEK(super CA)), dominant negative I(kappa)B kinase 2 (IKK(super DN)), and constitutively active IKK2 (IKK(super CA)). Inhibiting ERK activity by Ras(super DN) over-expression rapidly induced the apoptosis of osteoclastlike cells (OCLs) formed in vitro, whereas ERK activation after the introduction of MEK(super CA) remarkably lengthened their survival by preventing spontaneous apoptosis. Neither inhibition nor activation of ERK affected the bone-resorbing activity of OCLs. Inhibition of NF-(kappa)B pathway with IKK(super DN) virus suppressed the pit-forming activity of OCLs and NF-(kappa)B activation by IKK(super CA) expression upregulated it without affecting their survival. Interleukin lot (IL-1(alpha)) strongly induced ERK activation as well as NF-(kappa)B activation. Ras(super DN) virus partially inhibited ERK activation, and OCL survival promoted by IL-1(alpha). Inhibiting NF-(kappa)B activation by IKK(super DN) virus significantly suppressed the pit-forming activity enhanced by IL-1(alpha). These results indicate that ERK and NF-(kappa)B regulate different aspects of osteoclast activation: ERK is responsible for osteoclast survival, whereas NF-(kappa)B regulates osteoclast activation for bone resorption.