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© The Rockefeller University Press, 0021-9525/2000//333 $5.00
The Journal of Cell Biology, Volume 148, Number 2, , 2000 333-342

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

^a Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
^b Third Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
^c Laboratory of Molecular Genetics, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan
^d Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037
Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.81-3-3818-408281-3-3815-5411 ext 3375

tanakas-ort{at}h.u-tokyo.ac.jp

To examine the role of mitogen-activated protein kinase and nuclear factor kappa B (NF-B) 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 IB 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-B pathway with IKK^DN virus suppressed the pit-forming activity of OCLs and NF-B activation by IKK^CA expression upregulated it without affecting their survival. Interleukin 1 (IL-1) strongly induced ERK activation as well as NF-B activation. Ras^DN virus partially inhibited ERK activation, and OCL survival promoted by IL-1. Inhibiting NF-B activation by IKK^DN virus significantly suppressed the pit-forming activity enhanced by IL-1. These results indicate that ERK and NF-B regulate different aspects of osteoclast activation: ERK is responsible for osteoclast survival, whereas NF-B regulates osteoclast activation for bone resorption.

Key Words: osteoclast • adenovirus • apoptosis • Ras • NF-B

© 2000 The Rockefeller University Press

Abbreviations used in this paper: -MEM, -modified minimum essential medium; CSF, colony stimulating factor; EMSA, electrophoretic mobility shift assay; ERK, extracellular signal-regulated kinase; IKK, IB kinase; IL-1, interleukin 1; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase; MOI, multiplicity of infection; NF-B, nuclear factor kappa B; OCLs, osteoclast-like cells; TUNEL, Tdt-mediated dUTP dioxigenin nick-end labeling.

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