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Cited by 378Bone Metabolism and DiseasesRheumatoid Arthritis Research and TherapiesOsteomyelitis and Bone Disorders Research

Interleukin-18 (Interferon-γ–inducing Factor) Is Produced by Osteoblasts and Acts Via Granulocyte/Macrophage Colony-stimulating Factor and Not Via Interferon-γ to Inhibit Osteoclast Formation

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Udagawa, Nobuyuki, Horwood, Nicole J., Elliott, Jan, Mackay, Alan, Owens, Jane, Okamura, Haruki, Kurimoto, Masashi, Chambers, Timothy J. +2 more·1997·The Journal of Experimental Medicine
DOI 10.1084/jem.185.6.1005PMC PMC2196233
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Abstract

We have established by differential display polymerase chain reaction of mRNA that interleukin (IL)-18 is expressed by osteoblastic stromal cells. The stromal cell populations used for comparison differed in their ability to promote osteoclast-like multinucleated cell (OCL) formation. mRNA for IL-18 was found to be expressed in greater abundance in lines that were unable to support OCL formation than in supportive cells. Recombinant IL-18 was found to inhibit OCL formation in cocultures of osteoblasts and hemopoietic cells of spleen or bone marrow origin. IL-18 inhibited OCL formation in the presence of osteoclastogenic agents including 1α,25-dihydroxyvitamin D3, prostaglandin E2, parathyroid hormone, IL-1, and IL-11. The inhibitory effect of IL-18 was limited to the early phase of the cocultures, which coincides with proliferation of hemopoietic precursors. IL-18 has been reported to induce interferon-γ (IFN-γ) and granulocyte/macrophage colony-stimulating factor (GM–CSF) production in T cells, and both agents also inhibit OCL formation in vitro. Neutralizing antibodies to GM–CSF were able to rescue IL-18 inhibition of OCL formation, whereas neutralizing antibodies to IFN-γ did not. In cocultures with osteoblasts and spleen cells from IFN-γ receptor type II–deficient mice, IL-18 was found to inhibit OCL formation, indicating that IL-18 acted independently of IFN-γ production: IFN-γ had no effect in these cocultures. Additionally, in cocultures in which spleen cells were derived from receptor-deficient mice and osteoblasts were from wild-type mice and vice versa, we identified that the target cells for IFN-γ inhibition of OCL formation were the hemopoietic cells. The work provides evidence that IL-18 is expressed by osteoblasts and inhibits OCL formation via GM–CSF production and not via IFN-γ production.

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  • IL-18 inhibits osteoclastogenesis by downregulating osteoblast production of M-CSF.

    “Using co-cultures of osteoblasts and hematopoietic cells, Udagawa and associates found that IL-18 inhibited osteoclastogenesis by downregulating osteoblast production of M-CSF [48].”

    From Osteoclasts and Microgravity (2020) · cites this paper as [48]

    The Results section, “IL-18 Inhibits OCL Formation Via GM–CSF” (page unavailable), attributes the inhibition to increased production of GM–CSF. It does not identify downregulation of osteoblast M-CSF production as the mechanism; M-CSF and GM–CSF are different factors. (LLM, conf=0.90)

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Research works printed but not linked: 5

  1. [1]Suda, T., N. Takahashi, and T.J. Martin. 1995. Modulation of osteoclast differentiation: update. In Endocrine Review Monographs. Vol. 4. D.D. Bikle and A. Negrovilar, editors. Endocrine Society, Bethesda, MD. 266–270.
  2. [3]Suda, T., N. Udagawa, and N. Takahashi. 1996. Cells of bone: osteoclast generation. In Principles of Bone Biology. J.P. Billezikian, L.G. Raisz, G.A. Rodan, editors. Academic Press, San Diego, CA. 87–102.
  3. [11]Xu LX Kukita T Kukita A Otsuka T Niho Y Iijima T Interleukin-10 selectively inhibits osteoclastogenesis by inhibiting differentiation of osteoclast progenitors into preoteoclast-like cells J Cell Physiol 1995 165 624 629 7593242
  4. [14]Horowitz, M.C., and J.A. Lorenzo. 1996. Local regulators of bone: IL-1, TNF, lymphotoxin, interferon-γ, IL-8, IL-10, IL-4, the LIF/IL-6 family, and additional cytokines. In Principles of Bone Biology. J.P. Billezikian, L.G. Raisz, G.A. Rodan, editors. Academic Press, San Diego, CA. 687–700.
  5. [30]Suda N Gillespie MT Traianedes K Zhou H Ho PWM Hards DK Allan EH Martin TJ Moseley JM Expression of parathyroid hormone–related protein in cells of osteoblast lineage J Cell Physiol 1996 166 94 104 8557780

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Authors
Udagawa, N., Horwood, N. J., Elliott, J., Mackay, A., Owens, J., Okamura, H., Kurimoto, M., Chambers, T. J., Martin, T. J., & Gillespie, M. T.
Affiliations
Hyogo Medical University (JP)
ORCID
Venue
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
1997-03-17
Volume
185
Issue
6
Pages
1005-1012
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.185.6.1005
PMC
PMC2196233
OpenAlex
W2119656862
Cited by
378
References
35
Citations by year
2026: 1 · 2025: 2 · 2024: 5 · 2023: 7 · 2022: 2 · 2021: 6 · 2020: 7 · 2019: 3 · 2018: 3 · 2017: 4 · 2016: 7 · 2015: 3 · 2014: 10 · 2013: 9 · 2012: 13
FWCI
9.02
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • St George's Online Research Archive (St George's University of London) (acceptedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc-sa)
  • UEA Digital Repository (University of East Anglia) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
  • Health Sciences › Medicine › Rheumatology › Osteomyelitis and Bone Disorders Research
Keywords
IL-18, osteoblasts, osteoclastogenesis, osteoclast-like multinucleated cells, GM-CSF, interferon-gamma, bone remodeling, osteoclastogenesis inhibition
MeSH terms
Interferon gamma Receptor, Animals, Animals, Newborn, Base Sequence, Bone Marrow Cells, Cell Differentiation, Interferon-gamma, Male, Mice, Inbred C57BL, Molecular Sequence Data, Osteoblasts, Osteoclasts, Recombinant Proteins, RNA, Messenger, Transcription, Genetic, Polymerase Chain Reaction, Granulocyte-Macrophage Colony-Stimulating Factor, Cytokines, Interleukin-11, Receptors, Interferon, Mice, Knockout, Coculture Techniques, Interleukin-18, Mice

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