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 con structed adenovirus vectors carrying various mutants of signaling molecules : dominant negative Ras (Ras(DN)), constitutively active MEK1 (MEKCA), domi nant negative I kappa B kinase 2 (IKKDN), and constitutively active IKK2 (I KKCA). Inhibiting ERK activity by Ras(DN) over-expression rapidly induced t he apoptosis of osteoclastlike cells (OCLs) formed in vitro, whereas ERK ac tivation after the introduction of MEKCA remarkably lengthened their surviv al by preventing spontaneous apoptosis. Neither inhibition nor activation o f ERK affected the bone-resorbing activity of OCLs, Inhibition of NF-kappa B pathway with IKKDN virus suppressed the pit-forming activity of OCLs and NF-kappa B activation by IKKCA expression upregulated it without affecting their survival. Interleukin 1 alpha (IL-1 alpha) strongly induced ERK activ ation as well as NF-kappa B activation. Ras(DN) virus partially inhibited E RK activation, and OCL survival promoted by IL-1 alpha. Inhibiting NF-kappa B activation by IKKDN virus significantly suppressed the pit-forming activ ity 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 fo r bone resorption.