Nitric oxide: a cytokine-induced regulator of bone resorption

J Bone Miner Res. 1995 Jul;10(7):1040-9. doi: 10.1002/jbmr.5650100708.

Abstract

Nitric oxide (NO) has been reported to inhibit osteoclastic bone resorption, yet potent stimulators of bone resorption, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), are known to stimulate NO production. This paradox prompted us to reinvestigate the relationship between NO production and bone resorption in mouse calvarial organ cultures. Control cultures and those stimulated with calciotropic hormones and individual cytokines produced little NO, and under these conditions the NO synthase inhibitor, L-NG-monomethyl arginine (LMMA), had no significant effect on bone resorption. Cytokine combinations were much more potent stimulators of NO production than individual cytokines. Dramatic stimulation of NO production and inhibition of bone resorption resulted when gamma-interferon (IFN) was combined with IL-1 or TNF and these effects were reversed by LMMA. IFN had no effect on bone resorption and little effect on NO production when used alone or in combination with calciotropic hormones, however, suggesting that IFN selectively inhibits cytokine-induced bone resorption by generating large amounts of NO. IL-1 and TNF acted together to stimulate NO production but to a lesser degree than when combined with IFN. LMMA inhibited bone resorption induced by IL-1 and TNF, suggesting that lower concentrations of NO stimulate bone resorption. Experiments with the pharmacological NO donor S-nitroso-acetyl-penicillamine (SNAP) supported this view in showing generalized suppression of bone resorption at high SNAP concentrations, but potentiation of IL-1 induced bone resorption at lower SNAP concentrations. We conclude that cytokines are potent inducers of NO in bone and that cytokine-induced NO production has biphasic effects on bone resorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginine / analogs & derivatives
  • Arginine / pharmacology
  • Arginine / therapeutic use
  • Base Sequence
  • Bone Resorption / drug therapy
  • Bone Resorption / genetics
  • Bone Resorption / physiopathology*
  • Calcium / metabolism
  • Cytokines / pharmacology*
  • Cytokines / therapeutic use
  • DNA Primers / chemistry
  • Dinoprostone / metabolism
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Interferon-gamma / pharmacology
  • Interferon-gamma / therapeutic use
  • Interleukin-1 / pharmacology
  • Interleukin-1 / therapeutic use
  • Mice
  • Molecular Sequence Data
  • Nitric Oxide / biosynthesis
  • Nitric Oxide / physiology*
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase / genetics
  • Organ Culture Techniques
  • Osteoclasts / cytology
  • Osteoclasts / drug effects*
  • Penicillamine / analogs & derivatives
  • Penicillamine / pharmacology
  • Penicillamine / therapeutic use
  • Polymerase Chain Reaction
  • RNA / analysis
  • RNA / metabolism
  • Recombinant Proteins / pharmacology
  • Recombinant Proteins / therapeutic use
  • S-Nitroso-N-Acetylpenicillamine
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Necrosis Factor-alpha / therapeutic use
  • omega-N-Methylarginine

Substances

  • Cytokines
  • DNA Primers
  • Enzyme Inhibitors
  • Interleukin-1
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • omega-N-Methylarginine
  • Nitric Oxide
  • RNA
  • S-Nitroso-N-Acetylpenicillamine
  • Interferon-gamma
  • Arginine
  • Nitric Oxide Synthase
  • Penicillamine
  • Dinoprostone
  • Calcium