This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited 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 Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sunyer, T. Articles by Collin-Osdoby, P. Search for Related Content PubMed PubMed Citation Articles by Sunyer, T. Articles by Collin-Osdoby, P.

Ca²⁺ or Phorbol Ester But Not Inflammatory Stimuli Elevate Inducible Nitric Oxide Synthase Messenger Ribonucleic Acid and Nitric Oxide (NO) Release in Avian Osteoclasts: Autocrine NO Mediates Ca²⁺-Inhibited Bone Resorption¹

Department of Biology and Division of Bone and Mineral Research, Washington University, St. Louis, Missouri 63130

Address all correspondence and requests for reprints to: Patricia Collin-Osdoby, Department of Biology, Box 1229, Washington Uni-versity, St. Louis, Missouri 63130. E-mail: collin{at}biodec.wustl.edu

Osteoclast bone resorption is essential for normal calcium homeostasis and is therefore tightly controlled by calciotropic hormones and local modulatory cytokines and factors. Among these is nitric oxide (NO), a multifunctional free radical that potently inhibits osteoclast bone resorption in vitro and in vivo. Previous findings led us to propose that NO might serve as an autocrine, as well as paracrine, regulator of osteoclast function. This premise was investigated using isolated bone-resorptive avian osteoclasts and focusing on the inducible isoform of NO synthase (iNOS) responsible for inflammatory stimulated high-level NO synthesis in other cells. Avian osteoclasts expressed both iNOS messenger RNA (mRNA) and protein. However, inflammatory cytokines that induce iNOS mRNA, protein, and NO in other cells did not do so in avian osteoclasts, consistent with the known role of inflammatory stimuli in promoting osteoclast resorption and localized bone loss. In searching for potential modulators of osteoclast iNOS, protein kinase C activation [by phorbol 12-myristate 13-acetate (PMA)] and intracellular Ca²⁺ rises (A23187) were each found to elevate osteoclast iNOS mRNA and protein levels, while increasing NO release and reducing osteoclast bone resorption. The iNOS selective inhibitor aminoguanidine suppressed stimulated osteoclast NO production elicited by either signal, but reversed only the resorption inhibition due to raised Ca²⁺. Thus, whereas additional inhibitory signals are presumably coproduced in osteoclasts treated with PMA, osteoclast iNOS-derived NO may act as an autocrine signal to mediate Ca²⁺-inhibited bone resorption. These findings document for the first time an iNOS whose mRNA levels are regulated by Ca²⁺ or PMA, but not inflammatory stimuli, and the autocrine production of NO as a Ca²⁺ sensing signal to suppress osteoclast bone resorption. The unusual regulation of osteoclast iNOS makes it a potentially attractive target for designing novel therapeutic agents to alleviate excessive bone loss.

This article has been cited by other articles:

				H. Zheng, X. Yu, P. Collin-Osdoby, and P. Osdoby RANKL Stimulates Inducible Nitric-oxide Synthase Expression and Nitric Oxide Production in Developing Osteoclasts: AN AUTOCRINE NEGATIVE FEEDBACK MECHANISM TRIGGERED BY RANKL-INDUCED INTERFERON-beta VIA NF-{kappa}B THAT RESTRAINS OSTEOCLASTOGENESIS AND BONE RESORPTION J. Biol. Chem., June 9, 2006; 281(23): 15809 - 15820. [Abstract] [Full Text] [PDF]

				J. Aguirre, L. Buttery, M. O'Shaughnessy, F. Afzal, I. Fernandez de Marticorena, M. Hukkanen, P. Huang, I. MacIntyre, and J. Polak Endothelial Nitric Oxide Synthase Gene-Deficient Mice Demonstrate Marked Retardation in Postnatal Bone Formation, Reduced Bone Volume, and Defects in Osteoblast Maturation and Activity Am. J. Pathol., January 1, 2001; 158(1): 247 - 257. [Abstract] [Full Text] [PDF]

				K. S. Bauer, K. J. Cude, S. C. Dixon, E. A. Kruger, and W. D. Figg Carboxyamido-triazole Inhibits Angiogenesis by Blocking the Calcium-Mediated Nitric-Oxide Synthase-Vascular Endothelial Growth Factor Pathway J. Pharmacol. Exp. Ther., January 1, 2000; 292(1): 31 - 37. [Abstract] [Full Text]

				T. Umino, E. Kusano, S. Muto, T. Akimoto, S. Yanagiba, S. Ono, M. Amemiya, Y. Ando, S. Homma, U. Ikeda, et al. AVP inhibits LPS- and IL-1beta -stimulated NO and cGMP via V1 receptor in cultured rat mesangial cells Am J Physiol Renal Physiol, March 1, 1999; 276(3): F433 - F441. [Abstract] [Full Text] [PDF]

				M. G. Mohaupt, T. Fischer, J. Schwobel, R. B. Sterzel, and E. Schulze-Lohoff Activation of purinergic P2Y2 receptors inhibits inducible NO synthase in cultured rat mesangial cells Am J Physiol Renal Physiol, July 1, 1998; 275(1): F103 - F110. [Abstract] [Full Text] [PDF]

				R. Muniyappa, P. R. Srinivas, J. L. Ram, M. F. Walsh, and J. R. Sowers Calcium and Protein Kinase C Mediate High-Glucose-Induced Inhibition of Inducible Nitric Oxide Synthase in Vascular Smooth Muscle Cells Hypertension, January 1, 1998; 31(1): 289 - 295. [Abstract] [Full Text] [PDF]