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MKK3/6-p38 MAPK Signaling Is Required for IL-1β and TNF-α-Induced RANKL Expression in Bone Marrow Stromal Cells | Abstract Skip Navigation
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Journal of Interferon & Cytokine Research

MKK3/6-p38 MAPK Signaling Is Required for IL-1β and TNF-α-Induced RANKL Expression in Bone Marrow Stromal Cells

To cite this article:
Carlos Rossa, Jr., Kathryn Ehmann, Min Liu, Chetan Patil, and Dr. Keith L. Kirkwood. Journal of Interferon & Cytokine Research. October 2006, 26(10): 719-729. https://doi.org/10.1089/jir.2006.26.719

Published in Volume: 26 Issue 10: October 10, 2006

Author information

Carlos Rossa Jr.
Department of Diagnosis and Surgery, State University of Sao Paulo (UNESP), Araraquara, SP, Brazil.
Kathryn Ehmann
Department of Oral Biology, State University of New York at Buffalo, Buffalo, NY 14214.
Min Liu
Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI 48109.
Chetan Patil
Department of Oral Biology, State University of New York at Buffalo, Buffalo, NY 14214.
Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI 48109.
Dr. Keith L. Kirkwood
Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI 48109.

ABSTRACT

Coupled bone turnover is directed by the expression of receptor-activated NF-κB ligand (RANKL) and its decoy receptor, osteoprotegerin (OPG). Proinflammatory cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) induce RANKL expression in bone marrow stromal cells. Here, we report that IL-1β and TNF-α-induced RANKL requires p38 mitogen-activating protein kinase (MAPK) pathway activation for maximal expression. Real-time PCR was used to assess the p38 contribution toward IL-1β and TNF-α-induced RANKL mRNA expression. Steady-state RANKL RNA levels were increased approximately 17-fold by IL-1β treatment and subsequently reduced ∼70%–90% when p38 MAPK was inhibited with SB203580. RANKL mRNA stability data indicated that p38 MAPK did not alter the rate of mRNA decay in IL-1β-induced cells. Using a RANKL-luciferase cell line receptor containing a 120-kB segment of the 5' flanking region of the RANKL gene, reporter expression was stimulated 4–5-fold by IL-1β or TNF-α treatment. IL-1β-induced RANKL reporter expression was completely blocked with specific p38 inhibitors as well as dominant negative mutant constructs of MAPK kinase-3 and -6. In addition, blocking p38 signaling in bone marrow stromal cells partially inhibited IL-1β and TNF-α-induced osteoclastogenesis in vitro. Results from these studies indicate that p38 MAPK is a major signaling pathway involved in IL-1β and TNF-α-induced RANKL expression in bone marrow stromal cells.

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