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Cited by 215Bone Metabolism and DiseasesNF-κB Signaling PathwaysImmune Response and Inflammation

Determination of Three Isoforms of the Receptor Activator of Nuclear Factor-κΒ Ligand and Their Differential Expression in Bone and Thymus*

Ikeda, Tohru, Kasai, Michiyuki, Utsuyama, Masanori, Hirokawa, Katsuiku·2001·Endocrinology
DOI 10.1210/endo.142.4.8070
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Abstract

The receptor activator of nuclear factor (NF)-κB ligand [RANKL; also known as tumor necrosis factor-related activation-induced cytokine, osteoprotegerin ligand, and osteoclast differentiation factor] is known to bind with the receptor activator of NF-κB (RANK) and act not only as a key factor for osteoclastogenesis but also as a regulator of lymphocyte development. In this study, we found two additional isoforms of RANKL. RANKL 2 has a shorter intracellular domain than the original RANKL (RANKL 1), and RANKL 3 lacks a transmembrane domain and was thought to act as a soluble form. In the bone marrow stromal cell line ST2 and preosteoblastic cell line MC3T3-E1, all three RANKL isoforms were detected, but the expression of RANKL 2 was preferentially suppressed by treatment with 1α,25-dihydroxyvitamin D3 and dexamethasone. In young adult thymus, CD4−CD8− double-negative cells were positive for all three isoforms, CD4+CD8+ double-positive cells were positive for RANKL 1 and RANKL 3 but negative for RANKL 2, and CD4+CD8− and CD4−CD8+ single-positive cells were positive for all three isoforms. Immunofluorescence analyses of NIH3T3 cells transfected with each RANKL isoform indicated that the three RANKL isoforms were translated, and RANKL 2 protein predominantly stayed in the endoplasmic reticulum and Golgi networks. These results indicate that there are three kinds of RANKL-RANK pathways. The presence of multiple RANKL-RANK pathways suggests a more complicated RANKL-RANK system for osteoclastogenesis or T cell differentiation than previously thought.

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Crossref · 10.1210/endo.142.4.8070

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  • RANKL has at least three forms, two of which possess a transmembrane domain and can be cleaved into soluble forms with osteoclast-stimulating activity.

    “There are at least three forms of RANKL, two of which possess a transmembrane domain that positions the biologically active carboxy-terminus to the extracellular domain (i.e., a type II transmembrane protein) (Fig. 2).One of these forms, RANKL2, is a shorter alternative splicing variant of RANKL1 (44).Both of these variants can remain on cell surfaces or can be proteolytically cleaved into soluble”

    From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [44]

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Authors
Ikeda, T., Kasai, M., Utsuyama, M., & Hirokawa, K.
Affiliations
  • Tokyo Medical and Dental University (JP)
  • National Institute of Infectious Diseases (JP)
Corresponding author
Ikeda, Tohru
ORCID
Ikeda, Tohru
Venue
Endocrinology
Publisher
The Endocrine Society
Published
2001-04-01
Volume
142
Issue
4
Pages
1419-1426
ISSN
  • 0013-7227 (ISSN-L)
  • 1945-7170
DOI
10.1210/endo.142.4.8070
OpenAlex
W2047425473
Cited by
215
References
27
Citations by year
2026: 2 · 2025: 7 · 2024: 7 · 2023: 6 · 2022: 9 · 2021: 10 · 2020: 11 · 2019: 10 · 2018: 6 · 2017: 8 · 2016: 9 · 2015: 5 · 2014: 9 · 2013: 11 · 2012: 11
FWCI
2.68
Type
journal article
Language
en
Open access
closed
Locations
  • Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
Funders
Tokyo Medical and Dental University
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
RANKL, RANK/RANKL signaling, osteoclastogenesis, thymus, T cell differentiation, mesenchymal stem cells, 1,25-dihydroxyvitamin D3, dexamethasone, endoplasmic reticulum retention, double-negative thymocytes, double-positive thymocytes
MeSH terms
Amino Acid Sequence, Animals, Base Sequence, Bone and Bones, Carrier Proteins, Cell Differentiation, Cells, Cultured, Cloning, Molecular, Isomerism, Membrane Glycoproteins, Mice, Inbred C57BL, Microscopy, Fluorescence, Molecular Sequence Data, Osteoclasts, Thymus Gland, Tumor Necrosis Factor-alpha, Blotting, Northern, T-Lymphocyte Subsets, DNA, Complementary, Receptors, Tumor Necrosis Factor, Reverse Transcriptase Polymerase Chain Reaction, Mice, Rats, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B

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