Reciprocal Role of ERK and Nf-κb Pathways in Survival and Activation of Osteoclasts

To examine the role of mitogen-activated protein kinase and nuclear factor kappa B (NF-κB) pathways on osteoclast survival and activation, we constructed adenovirus vectors carrying various mutants of signaling molecules: dominant negative Ras (Ras(DN)), constitutively active MEK1 (MEK(CA)), dominant negative IκB kinase 2 (IKK(DN)), and constitutively active IKK2 (IKK(CA)). Inhibiting ERK activity by Ras(DN) overexpression rapidly induced the apoptosis of osteoclast-like cells (OCLs) formed in vitro, whereas ERK activation after the introduction of MEK(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-κB pathway with IKK(DN) virus suppressed the pit-forming activity of OCLs and NF-κB activation by IKK(CA) expression upregulated it without affecting their survival. Interleukin 1α (IL-1α) strongly induced ERK activation as well as NF-κB activation. Ras(DN) virus partially inhibited ERK activation, and OCL survival promoted by IL-1α. Inhibiting NF-κB activation by IKK(DN) virus significantly suppressed the pit-forming activity enhanced by IL-1α. These results indicate that ERK and NF-κB regulate different aspects of osteoclast activation: ERK is responsible for osteoclast survival, whereas NF-κB regulates osteoclast activation for bone resorption.