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

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 NFkappaB and in NFkappaB-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 NFkappaB in osteoclast precursors.

[1]  B. Morris,et al.  Activation of nuclear factor kappaB by nitric oxide in rat striatal neurones: differential inhibition of the p50 and p65 subunits by dexamethasone. , 2002, Journal of neurochemistry.

[2]  W. Dougall,et al.  RANK is essential for osteoclast and lymph node development. , 1999, Genes & development.

[3]  D. Lacey,et al.  Interleukin-1β and tumor necrosis factor-α, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells , 1999 .

[4]  S. Morony,et al.  TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. , 1999, Genes & development.

[5]  B. Brüne,et al.  NF-κB and AP-1 Activation by Nitric Oxide Attenuated Apoptotic Cell Death in RAW 264.7 Macrophages , 1999 .

[6]  J. Polak,et al.  Cytokine-induced Prostaglandin E2 Synthesis and Cyclooxygenase-2 Activity Are Regulated Both by a Nitric Oxide-dependent and -independent Mechanism in Rat Osteoblasts in Vitro * , 1999, The Journal of Biological Chemistry.

[7]  Z Domljan,et al.  Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. , 1998, Arthritis and rheumatism.

[8]  C. Lowenstein,et al.  Impaired liver regeneration in inducible nitric oxide synthasedeficient mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[9]  T. Hofmann,et al.  Co‐stimulatory effect of nitric oxide on endothelial NF‐κB implies a physiological self‐amplifying mechanism , 1998 .

[10]  G. Gronowicz,et al.  Mice lacking the type I interleukin-1 receptor do not lose bone mass after ovariectomy. , 1998, Endocrinology.

[11]  D. Lacey,et al.  Osteoprotegerin Ligand Is a Cytokine that Regulates Osteoclast Differentiation and Activation , 1998, Cell.

[12]  C. Lowenstein,et al.  The role of inducible nitric oxide synthase in the host response to Coxsackievirus myocarditis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[13]  P. Baeuerle.  Pro-inflammatory signaling: Last pieces in the NF-κB puzzle? , 1998, Current Biology.

[14]  I. McInnes,et al.  Septic arthritis following Staphylococcus aureus infection in mice lacking inducible nitric oxide synthase. , 1998, Journal of immunology.

[15]  Ulrich Siebenlist,et al.  Requirement for NF-κB in osteoclast and B-cell development , 1997 .

[16]  P. Feng,et al.  IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. , 1997, Science.

[17]  J. Caamaño,et al.  Osteopetrosis in mice lacking NF-κB1 and NF-κB2 , 1997, Nature Medicine.

[18]  S. Ralston,et al.  Cytokine‐Induced Nitric Oxide Inhibits Bone Resorption by Inducing Apoptosis of Osteoclast Progenitors and Suppressing Osteoclast Activity , 1997, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[19]  Matthias Mann,et al.  IKK-1 and IKK-2: Cytokine-Activated IκB Kinases Essential for NF-κB Activation , 1997 .

[20]  G Shimamoto,et al.  Osteoprotegerin: A Novel Secreted Protein Involved in the Regulation of Bone Density , 1997, Cell.

[21]  David Baltimore,et al.  NF-κB: Ten Years After , 1996, Cell.

[22]  S. Dower,et al.  Modulation of osteoclast-activating factor activity of multiple myeloma bone marrow cells by different interleukin-1 inhibitors. , 1996, Experimental hematology.

[23]  D. Reid,et al.  Elevated nitric oxide production in rheumatoid arthritis. Detection using the fasting urinary nitrate:creatinine ratio. , 1996, Arthritis and rheumatism.

[24]  C. Dinarello,et al.  Biologic basis for interleukin-1 in disease. , 1996, Blood.

[25]  J. Polak,et al.  Cytokine-stimulated expression of inducible nitric oxide synthase by mouse, rat, and human osteoblast-like cells and its functional role in osteoblast metabolic activity. , 1995, Endocrinology.

[26]  P. W. Johnston,et al.  Nitric oxide: A cytokine‐induced regulator of bone resorption , 1995, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[27]  I. Charles,et al.  Altered immune responses in mice lacking inducible nitric oxide synthase , 1995, Nature.

[28]  S. F. Pearce,et al.  Nitric Oxide-stimulated Guanine Nucleotide Exchange on p21ras(*) , 1995, The Journal of Biological Chemistry.

[29]  J M Polak,et al.  Bidirectional regulation of osteoclast function by nitric oxide synthase isoforms. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[30]  A. van der Plas,et al.  Characteristics and properties of osteocytes in culture , 1994, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[31]  S. Ralston,et al.  Human osteoblast-like cells produce nitric oxide and express inducible nitric oxide synthase. , 1994, Endocrinology.

[32]  P. Nibbering,et al.  Inducible production of nitric oxide in osteoblast-like cells and in fetal mouse bone explants is associated with suppression of osteoclastic bone resorption. , 1994, The Journal of clinical investigation.

[33]  C. Evans,et al.  Nitric oxide and arthritis. , 1993, Arthritis and rheumatism.

[34]  C. Lowenstein,et al.  Cytokines, endotoxin, and glucocorticoids regulate the expression of inducible nitric oxide synthase in hepatocytes. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[35]  D. Peterson,et al.  The non specificity of specific nitric oxide synthase inhibitors. , 1992, Biochemical and biophysical research communications.

[36]  N. Andrews,et al.  A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. , 1991, Nucleic acids research.

[37]  H. Datta,et al.  Osteoclastic inhibition: an action of nitric oxide not mediated by cyclic GMP. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[38]  G. Mundy,et al.  Effects of interleukin-1 on bone turnover in normal mice. , 1989, Endocrinology.

[39]  T. Martin,et al.  Osteoblastic cells are involved in osteoclast formation. , 1988, Endocrinology.

[40]  M. Grynpas,et al.  Fluoride reduces the rate of dissolution of bone. , 1988, Bone and mineral.

[41]  A. Parfitt.  Bone histomorphometry: standardization of nomenclature, symbols and units (summary of proposed system). , 1988, Bone.

[42]  F. Dewhirst,et al.  Synergism between parathyroid hormone and interleukin 1 in stimulating bone resorption in organ culture , 1987, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[43]  F. Dewhirst,et al.  Purification and partial sequence of human osteoclast-activating factor: identity with interleukin 1 beta. , 1985, Journal of immunology.

[44]  R. Russell,et al.  An interleukin 1 like factor stimulates bone resorption in vitro , 1983, Nature.