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Am J Physiol Endocrinol Metab 278: E1031-E1037, 2000;
0193-1849/00 $5.00
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Vol. 278, Issue 6, E1031-E1037, June 2000

Peroxynitrite production by TNF-alpha and IL-1beta : implication for suppression of osteoblastic differentiation

Hisako Hikiji1,3, Wee Soo Shin2,3, Toshiyuki Koizumi1, Tsuyoshi Takato1, Takafumi Susami1, Yoko Koizumi1,3, Yoko Okai-Matsuo2, and Teruhiko Toyo-Oka2,3

1 Department of Oral and Maxillofacial Surgery, 2 Second Department of Internal Medicine, Faculty of Medicine, and 3 Health Service Center, University of Tokyo, Bunkyo-ku, Tokyo 113-8865, Japan

To determine the roles of nitric oxide (NO) and its metabolite, peroxynitrite (ONOO-), on osteoblastic activation, we investigated the effects of a NO donor [ethanamine, 2,2'-(hydroxynitrosohydrazono)bis- (dNO)], an O-2 donor (pyrogallol), and an ONOO- scavenger (urate) on alkaline phosphatase (ALPase) activity and osteocalcin gene expression, which are indexes of osteoblastic differentiation. dNO elevated ALPase activity in the osteogenic MC3T3-E1 cell line. The combination of dNO and pyrogallol reduced both ALPase activity and osteocalcin gene expression. Because both indexes were recovered by urate, ONOO-, unlike NO itself, inhibited the osteoblastic differentiation. Furthermore, treatment with a combination of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha ) and interleukin-1beta (IL-1beta ) was found to yield ONOO- as well as NO and O-2. The reductions in ALPase activity and osteocalcin gene expression were also restored by urate. We conclude that ONOO- produced by TNF-alpha and IL-1beta , but not NO per se, would overcome the stimulatory effect of NO on osteoblastic activity and inhibit osteoblastic differentiation.

nitric oxide; osteoblasts; proinflammatory cytokines


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T. Abe, H. Hikiji, W. S. Shin, N. Koshikiya, S.-i. Shima, J. Nakata, T. Susami, T. Takato, and T. Toyo-oka
Targeting of iNOS with antisense DNA plasmid reduces cytokine-induced inhibition of osteoblastic activity
Am J Physiol Endocrinol Metab, September 1, 2003; 285(3): E614 - E621.
[Abstract] [Full Text] [PDF]


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