HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 23, 15809-15820, June 9, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/23/15809    most recent M513225200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zheng, H. Articles by Osdoby, P. Search for Related Content PubMed PubMed Citation Articles by Zheng, H. Articles by Osdoby, P. Social Bookmarking                      What's this?

RANKL Stimulates Inducible Nitric-oxide Synthase Expression and Nitric Oxide Production in Developing Osteoclasts

AN AUTOCRINE NEGATIVE FEEDBACK MECHANISM TRIGGERED BY RANKL-INDUCED INTERFERON- VIA NF-B THAT RESTRAINS OSTEOCLASTOGENESIS AND BONE RESORPTION^*

From the Department of Biology and the Division of Bone and Mineral Metabolism, Washington University, St. Louis, Missouri 63130

Nitric oxide (NO) is a multifunctional signaling molecule and a key vasculoprotective and potential osteoprotective factor. NO regulates normal bone remodeling and pathological bone loss in part through affecting the recruitment, formation, and activity of bone-resorbing osteoclasts. Using murine RAW 264.7 and primary bone marrow cells or osteoclasts formed from them by receptor activator of NF-B ligand (RANKL) differentiation, we found that inducible nitric-oxide synthase (iNOS) expression and NO generation were stimulated by interferon (IFN)- or lipopolysaccharide, but not by interleukin-1 or tumor necrosis factor-. Surprisingly, iNOS expression and NO release were also triggered by RANKL. This response was time- and dose-dependent, required NF-B activation and new protein synthesis, and was specifically blocked by the RANKL decoy receptor osteoprotegerin. Preventing RANKL-induced NO (via iNOS-selective inhibition or use of marrow cells from iNOS^–/– mice) increased osteoclast formation and bone pit resorption, indicating that such NO normally restrains RANKL-mediated osteoclastogenesis. Additional studies suggested that RANKL-induced NO inhibition of osteoclast formation does not occur via NO activation of a cGMP pathway. Because IFN- is also a RANKL-induced autocrine negative feedback inhibitor that limits osteoclastogenesis, we investigated whether IFN- is involved in this novel RANKL/iNOS/NO autoregulatory pathway. IFN- was induced by RANKL and stimulated iNOS expression and NO release, and a neutralizing antibody to IFN- inhibited iNOS/NO elevation in response to RANKL, thereby enhancing osteoclast formation. Thus, RANKL-induced IFN- triggers iNOS/NO as an important negative feedback signal during osteoclastogenesis. Specifically targeting this novel autoregulatory pathway may provide new therapeutic approaches to combat various osteolytic bone diseases.

Received for publication, December 12, 2005 , and in revised form, March 16, 2006.

^* This work was supported in part by National Institutes of Health Grant AR42715 (to P. O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by Mineral and Skeletal Metabolism Training Grant 5 T32 AR07033-31 from the National Institutes of Health.

² To whom correspondence should be addressed: Dept. of Biology, Washington University, 1229 McDonnell Hall, P. O. Box 1229, St. Louis, MO 63130. Tel.: 314-935-4044; Fax: 314-935-5134; E-mail: osdoby{at}biology.wustl.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. R. Kiesel, Z. S. Buchwald, and R. Aurora Cross-Presentation by Osteoclasts Induces FoxP3 in CD8+ T Cells J. Immunol., May 1, 2009; 182(9): 5477 - 5487. [Abstract] [Full Text] [PDF]

				O. Uluckan, S. N. Becker, H. Deng, W. Zou, J. L. Prior, D. Piwnica-Worms, W. A. Frazier, and K. N. Weilbaecher CD47 Regulates Bone Mass and Tumor Metastasis to Bone Cancer Res., April 1, 2009; 69(7): 3196 - 3204. [Abstract] [Full Text] [PDF]

				B. Sung, A. Murakami, B. O. Oyajobi, and B. B. Aggarwal Zerumbone Abolishes RANKL-Induced NF-{kappa}B Activation, Inhibits Osteoclastogenesis, and Suppresses Human Breast Cancer-Induced Bone Loss in Athymic Nude Mice Cancer Res., February 15, 2009; 69(4): 1477 - 1484. [Abstract] [Full Text] [PDF]

				R. Modarresi, Z. Xiang, M. Yin, and J. Laurence WNT/{beta}-Catenin Signaling Is Involved in Regulation of Osteoclast Differentiation by Human Immunodeficiency Virus Protease Inhibitor Ritonavir: Relationship to Human Immunodeficiency Virus-Linked Bone Mineral Loss Am. J. Pathol., January 1, 2009; 174(1): 123 - 135. [Abstract] [Full Text] [PDF]

				H. Ha, J.-H. Lee, H.-N. Kim, H. B. Kwak, H.-M. Kim, S. E. Lee, J. H. Rhee, H.-H. Kim, and Z. H. Lee Stimulation by TLR5 Modulates Osteoclast Differentiation through STAT1/IFN-{beta} J. Immunol., February 1, 2008; 180(3): 1382 - 1389. [Abstract] [Full Text] [PDF]