Cytokine-Induced Nitric Oxide Inhibits Bone Resorption by Inducing Apoptosis of Osteoclast Progenitors and Suppressing Osteoclast Activity
- 1 November 1997
- journal article
- Published by Oxford University Press (OUP) in Journal of Bone and Mineral Research
- Vol. 12 (11) , 1797-1804
- https://doi.org/10.1359/jbmr.1997.12.11.1797
Abstract
Interferon-gamma (IFN-gamma) has been shown to inhibit interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) stimulated bone resorption by strongly stimulating nitric oxide (NO) synthesis. Here we studied the mechanisms underlying this inhibition. Osteoclasts were generated in 10-day cocultures of mouse osteoblasts and bone marrow cells and the effect of cytokine-induced NO on osteoclast formation and activity was determined. Stimulation of the cocultures with IL-1 beta, TNF-alpha and IFN-gamma markedly enhanced NO production by 50- to 70-fold, and this was found to be derived predominantly from the osteoblast cell layer. When high levels of NO were induced by cytokines during early stages of the cocultures, osteoclast formation was virtually abolished and bone resorption markedly inhibited. Cytokine stimulation during the latter stages of coculture also resulted in inhibition of bone resorption, but here the effects were mainly due to an inhibitory effect on osteoclast activity. At all stages, however, the inhibitory effects of cytokines on osteoclast formation and activity were blocked by the NO-synthase inhibitor L-NMMA. Further investigations suggested that the NO-mediated inhibition of osteoclast formation was due in part to apoptosis of osteoclast progenitors. Cytokine stimulation during the early stage of the culture caused a large increase in apoptosis of bone marrow cells, and these effects were blocked by L-NMMA and enhanced by NO donors. We found no evidence of apoptosis in osteoclasts exposed to high levels of cytokine-induced NO at any stage in the culture, however, or of apoptosis affecting mature osteoclasts exposed to high levels of NO, suggesting that immature cells in the bone marrow compartment are most sensitive to NO-induced apoptosis. In summary, these studies identify NO as a potentially important osteoblast-osteoclast coupling factor which has potent inhibitory effects on bone resorption. These actions, in turn, are mediated by inhibition of osteoclast formation probably due to NO-induced apoptosis of osteoclast progenitors and by inhibition of the resorptive activity of mature osteoclasts.Keywords
This publication has 15 references indexed in Scilit:
- Nitric oxide and boneJournal of Bone and Mineral Research, 1996
- Nitric oxide suppression of human hematopoiesis in vitro. Contribution to inhibitory action of interferon-gamma and tumor necrosis factor-alpha.Journal of Clinical Investigation, 1995
- Bidirectional regulation of osteoclast function by nitric oxide synthase isoforms.Proceedings of the National Academy of Sciences, 1995
- Expression and functional role of nitric oxide synthase in osteoblast-like cellsJournal of Bone and Mineral Research, 1995
- Human osteoblast-like cells produce nitric oxide and express inducible nitric oxide synthase.Endocrinology, 1994
- Cytokines Induce Nitric Oxide Production in Mouse OsteoblastsBiochemical and Biophysical Research Communications, 1994
- Potentiation of osteoclast bone-resorption activity by inhibition of nitric oxide synthase.Proceedings of the National Academy of Sciences, 1994
- Inducible production of nitric oxide in osteoblast-like cells and in fetal mouse bone explants is associated with suppression of osteoclastic bone resorption.Journal of Clinical Investigation, 1994
- The L-Arginine-Nitric Oxide PathwayNew England Journal of Medicine, 1993
- Osteoclastic inhibition: an action of nitric oxide not mediated by cyclic GMP.Proceedings of the National Academy of Sciences, 1991