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© The Rockefeller University Press, 0021-9525/2000/1/333/ $5.00
The Journal of Cell Biology, Volume 148, Number 2, January 24, 2000 333-342

Original Article

Reciprocal Role of ERK and NF-{kappa}B Pathways in Survival and Activation of Osteoclasts

Tsuyoshi Miyazakia, Hideki Katagirib, Yumi Kanegaec, Hiroshi Takayanagia, Yasuhiro Sawadaa, Aiichiro Yamamotoa, Mattew P. Pandod, Tomoichiro Asanob, Inder M. Vermad, Hiromi Odaa, Kozo Nakamuraa, and Sakae Tanakaa
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

Correspondence to: Sakae Tanaka, Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Tel:81-3-3815-5411 ext 3375 Fax:81-3-3818-4082 E-mail:tanakas-ort{at}h.u-tokyo.ac.jp.

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 (RasDN), constitutively active MEK1 (MEKCA), dominant negative I{kappa}B kinase 2 (IKKDN), and constitutively active IKK2 (IKKCA). Inhibiting ERK activity by RasDN overexpression rapidly induced the apoptosis of osteoclast-like cells (OCLs) formed in vitro, whereas ERK activation after the introduction of MEKCA 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 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 activation as well as NF-{kappa}B activation. RasDN virus partially inhibited ERK activation, and OCL survival promoted by IL-1{alpha}. Inhibiting NF-{kappa}B activation by IKKDN 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.

Key Words: osteoclast, adenovirus, apoptosis, Ras, NF-{kappa}B


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