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

R J van't Hof, K J Armour, L M Smith, K E Armour, X Q Wei, F Y Liew, S H Ralston

Research output: Contribution to journalArticle

118 Citations (Scopus)

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 NF kappa B and in NF kappa B-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 NF kappa B in osteoclast precursors.

Original languageEnglish
Pages (from-to)7993-7998
Number of pages6
JournalPNAS
Volume97
Publication statusPublished - 2000

Keywords

  • NF-KAPPA-B
  • OSTEOBLAST-LIKE CELLS
  • MICE LACKING
  • INTERLEUKIN-1 RECEPTOR
  • OSTEOPROTEGERIN LIGAND
  • RHEUMATOID-ARTHRITIS
  • ACTIVATING FACTOR
  • CYTOKINE
  • EXPRESSION
  • RAT

Cite this

van't Hof, R. J., Armour, K. J., Smith, L. M., Armour, K. E., Wei, X. Q., Liew, F. Y., & Ralston, S. H. (2000). Requirement of the inducible nitric oxide synthase pathway for IL-1-induced osteoclastic bone resorption. PNAS, 97, 7993-7998.

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, X Q ; Liew, F Y ; Ralston, S H .

In: PNAS, Vol. 97, 2000, p. 7993-7998.

Research output: Contribution to journalArticle

van't Hof, RJ, Armour, KJ, Smith, LM, Armour, KE, Wei, XQ, Liew, FY & Ralston, SH 2000, 'Requirement of the inducible nitric oxide synthase pathway for IL-1-induced osteoclastic bone resorption', PNAS, vol. 97, pp. 7993-7998.
van't Hof RJ, Armour KJ, Smith LM, Armour KE, Wei XQ, Liew FY et al. Requirement of the inducible nitric oxide synthase pathway for IL-1-induced osteoclastic bone resorption. PNAS. 2000;97:7993-7998.
van't Hof, R J ; Armour, K J ; Smith, L M ; Armour, K E ; Wei, X Q ; Liew, F Y ; Ralston, S H . / Requirement of the inducible nitric oxide synthase pathway for IL-1-induced osteoclastic bone resorption. In: PNAS. 2000 ; Vol. 97. pp. 7993-7998.
@article{e8174063a79e4eb0a4d4348f8d2617a5,
title = "Requirement of the inducible nitric oxide synthase pathway for IL-1-induced osteoclastic bone resorption",
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 NF kappa B and in NF kappa B-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 NF kappa B in osteoclast precursors.",
keywords = "NF-KAPPA-B, OSTEOBLAST-LIKE CELLS, MICE LACKING, INTERLEUKIN-1 RECEPTOR, OSTEOPROTEGERIN LIGAND, RHEUMATOID-ARTHRITIS, ACTIVATING FACTOR, CYTOKINE, EXPRESSION, RAT",
author = "{van't Hof}, {R J} and Armour, {K J} and Smith, {L M} and Armour, {K E} and Wei, {X Q} and Liew, {F Y} and Ralston, {S H}",
year = "2000",
language = "English",
volume = "97",
pages = "7993--7998",
journal = "PNAS",
issn = "0027-8424",
publisher = "NATL ACAD SCIENCES",

}

TY - JOUR

T1 - Requirement of the inducible nitric oxide synthase pathway for IL-1-induced osteoclastic bone resorption

AU - van't Hof, R J

AU - Armour, K J

AU - Smith, L M

AU - Armour, K E

AU - Wei, X Q

AU - Liew, F Y

AU - Ralston, S H

PY - 2000

Y1 - 2000

N2 - 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 NF kappa B and in NF kappa B-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 NF kappa B in osteoclast precursors.

AB - 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 NF kappa B and in NF kappa B-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 NF kappa B in osteoclast precursors.

KW - NF-KAPPA-B

KW - OSTEOBLAST-LIKE CELLS

KW - MICE LACKING

KW - INTERLEUKIN-1 RECEPTOR

KW - OSTEOPROTEGERIN LIGAND

KW - RHEUMATOID-ARTHRITIS

KW - ACTIVATING FACTOR

KW - CYTOKINE

KW - EXPRESSION

KW - RAT

M3 - Article

VL - 97

SP - 7993

EP - 7998

JO - PNAS

JF - PNAS

SN - 0027-8424

ER -