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Requirement of the inducible nitric oxide synthase pathway for IL-1-induced osteoclastic bone resorption

van't Hof, R. J., Armour, K. J., Smith, L. M, Armour, K. E., Wei, Xiao-Qing, Liew, Foo Y. and Ralston, S. H. 2000. Requirement of the inducible nitric oxide synthase pathway for IL-1-induced osteoclastic bone resorption. Proceedings of the National Academy of Sciences of the United States of America 97 (14) , pp. 7993-7998. 10.1073/pnas.130511497

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Abstract

Nitric oxide has been suggested to be involved in the regulation of bone turnover, especially in pathological conditions characterized by release of bone-resorbing cytokines. The cytokine IL-1 is thought to act as a mediator of periarticular bone loss and tissue damage in inflammatory diseases such as rheumatoid arthritis. IL-1 is a potent stimulator of both osteoclastic bone resorption and expression of inducible nitric oxide synthase (iNOS) in bone cells and other cell types. In this study, we investigated the role that the iNOS pathway plays in mediating the bone-resorbing effects of IL-1 by studying mice with targeted disruption of the iNOS gene. Studies in vitro and in vivo showed that iNOS-deficient mice exhibited profound defects of IL-1-induced osteoclastic bone resorption but responded normally to calciotropic hormones such as 1,25 dihydroxyvitamin D3 and parathyroid hormone. Immunohistochemical studies and electrophoretic mobility shift assays performed on bone marrow cocultures from iNOS-deficient mice showed abnormalities in IL-1-induced nuclear translocation of the p65 component of NFkappaB and in NFkappaB-DNA binding, which were reversed by treatment with the NO donor S-nitroso-acetyl penicillamine. These results show that the iNOS pathway is essential for IL-1-induced bone resorption and suggest that the effects of NO may be mediated by modulating IL-1-induced nuclear activation of NFkappaB in osteoclast precursors.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Dentistry
Subjects: R Medicine > R Medicine (General)
Publisher: National Academy of Sciences
ISSN: 0027-8424
Last Modified: 04 Jun 2017 04:16
URI: http://orca-mwe.cf.ac.uk/id/eprint/35672

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