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PMID: 10648566 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Reciprocal role of ERK and NF-kappaB pathways in survival and activation of osteoclasts.

The Journal of cell biology ·Vol. 148 ·No. 2 ·2000-01-24 ·Pages 333-42

Miyazaki T, Katagiri H, Kanegae Y, Takayanagi H, Sawada Y, Yamamoto A, Pando MP, Asano T, Verma IM, Oda H, Nakamura K, Tanaka S

Abstract

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

MeSH Terms
Adenoviridae/genetics Animals Apoptosis Biological Transport Cell Nucleus/metabolism Cell Survival Down-Regulation Genetic Vectors I-kappa B Kinase Interleukin-1/pharmacology Male Mice Mitogen-Activated Protein Kinase Kinases/genetics,metabolism Mitogen-Activated Protein Kinases/metabolism NF-kappa B/metabolism Osteoclasts/metabolism Protein Serine-Threonine Kinases/genetics,metabolism Signal Transduction Skull/cytology ras Proteins/genetics,metabolism
Chemicals
Interleukin-1 NF-kappa B Protein Serine-Threonine Kinases Chuk protein, mouse I-kappa B Kinase Ikbkb protein, mouse Ikbke protein, mouse Mitogen-Activated Protein Kinases Mitogen-Activated Protein Kinase Kinases ras Proteins
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Miyazaki T
Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
Katagiri H
Kanegae Y
Takayanagi H
Sawada Y
Yamamoto A
Pando M P
Asano T
Verma I M
Oda H
Nakamura K
Tanaka S
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.148.2.333
Published
2000-01-24
Pages
333-42
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2174281
Subset
IM
External Links
PubMed source DOI: 10.1083/jcb.148.2.333 PMC Full Text View journal details
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