Cited by 299Bone Metabolism and DiseasesTGF-β signaling in diseasesBone health and osteoporosis research

Transforming Growth Factor-β Stimulates the Production of Osteoprotegerin/Osteoclastogenesis Inhibitory Factor by Bone Marrow Stromal Cells

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Takai, Hiroyuki, Kanematsu, Masahiro, Yano, Kazuki, Tsuda, Eisuke, Higashio, Kanji, Ikeda, Kyoji, Watanabe, Ken, Yamada, Yoshiji·1998·Journal of Biological Chemistry

Abstract

Osteoprotegerin (OPG)/osteoclastogenesis inhibitory factor (OCIF) is a recently identified cytokine that belongs to the tumor necrosis factor receptor superfamily and regulates bone mass by inhibiting osteoclastic bone resorption. The present study was undertaken to determine whether OPG/OCIF is produced in bone microenvironment and how the expression is regulated. A transcript for OPG/OCIF at 3.1 kilobases was detected in bone marrow stromal cells (ST2 and MC3T3-G2/PA6) as well as in osteoblastic cells (MC3T3-E1). Transforming growth factor-beta1 (TGF-beta1) markedly increased the steady-state level of OPG/OCIF mRNA in a dose-dependent manner, while TGF-beta1 suppressed the mRNA expression of tumor necrosis factor-related activation-induced cytokine (TRANCE)/receptor activator of NF-kappaB ligand (RANKL), a positive regulator of osteoclastogenesis to which OPG/OCIF binds. The effect of TGF-beta1 on the expression of OPG/OCIF mRNA was transient, with a peak level at 3-6 h. The up-regulation of OPG/OCIF mRNA by TGF-beta1 in ST2 cells did not require de novo protein synthesis and involved both a transcriptional and a post-transcriptional mechanism. Western blot analysis and an enzyme-linked immunosorbent assay revealed that TGF-beta1 significantly increased the secretion of OPG/OCIF protein by ST2 cells at 6-24 h. In murine bone marrow cultures, TGF-beta1 markedly inhibited the formation of tartrate-resistant acid phosphatase-positive multinucleated osteoclast-like cells in the presence of 1,25-dihydroxyvitamin D3, whose effect was significantly reversed by a neutralizing antibody against OPG/OCIF. These results suggest that TGF-beta1 negatively regulates osteoclastogenesis, at least in part, through the induction of OPG/OCIF by bone marrow stromal cells and that the balance between OPG/OCIF and TRANCE/RANKL in local environment may be an important determinant of osteoclastic bone resorption.

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  • High TGF-β1 expression inhibits migration of osteoclast precursors by suppressing RANKL expression and stimulating OPG production in osteoblasts.

    “High TGF-β1 expression inhibits the migration of osteoclast precursors208 by suppressing RANKL expression and by stimulating OPG production in osteoblasts.209”

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Authors
Takai, H., Kanematsu, M., Yano, K., Tsuda, E., Higashio, K., Ikeda, K., Watanabe, K., & Yamada, Y.
Affiliations
Megmilk Snow Brand (Japan) (JP)
Corresponding author
Yamada, Yoshiji
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
1998-10
Volume
273
Issue
42
Pages
27091-27096
ISSN
0021-9258 (ISSN-L)
OpenAlex
W1994756823
Cited by
299
References
38
Citations by year
2026: 2 · 2025: 6 · 2024: 4 · 2023: 2 · 2022: 4 · 2021: 5 · 2020: 3 · 2019: 6 · 2018: 3 · 2017: 6 · 2016: 6 · 2015: 7 · 2014: 4 · 2013: 6 · 2012: 8
FWCI
7.44
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
Keywords
osteoprotegerin, TGF-β1, mesenchymal stem cells, RANKL, osteoclastogenesis, bone resorption, osteoblasts, transcriptional regulation, post-transcriptional regulation, osteoclast-like cells, 1,25-dihydroxyvitamin D3
MeSH terms
Animals, Bone Marrow Cells, Cell Differentiation, Cell Line, Dose-Response Relationship, Drug, Gene Expression Regulation, Glycoproteins, Models, Biological, Osteoclasts, RNA, Messenger, Transforming Growth Factor beta, Stromal Cells, Receptors, Tumor Necrosis Factor, Receptors, Cytoplasmic and Nuclear, Mice, Osteoprotegerin

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