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Cited by 63Bone Metabolism and DiseasesCellular transport and secretionCell death mechanisms and regulation

OPG/membranous–RANKL complex is internalized via the clathrin pathway before a lysosomal and a proteasomal degradation

Tat, Steeve Kwan, Padrines, Marc, Theoleyre, Sandrine, Couillaud-Battaglia, Severine, Heymann, Dominique, Redini, Françoise, Fortun, Yannick·2006·Bone
DOI 10.1016/j.bone.2006.03.016
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Abstract

The members of the OPG/RANK/RANKL (osteoprotegerin/receptor activator of nuclear factor kappaB/RANK ligand) triad are involved in various osteolytic pathologies such as bone tumors. Although many studies described the use of OPG during the treatment of bone diseases, its bioavailability and the mechanism by which the cells control the extracellular OPG remains blurred. The present work uses a strongly RANKL expressing cellular model to assess the becoming and the bioavailability of exogenous OPG in the context of its interactions with RANKL. The human kidney cell line 293, which initially expresses neither OPG nor RANKL, was stably transfected by the full length of mouse transmembranous form of RANKL (293RL). When OPG is incubated with 293RL cells, the extracellular concentration of OPG was strongly decreased in a time-dependent manner. The OPG disappearance was not inhibited by the addition of several proteases inhibitors, thus excluding any extracellular protease degradation. Contrary to previous results obtained on myeloma cells, which strongly express syndecan-1, the OPG disappearance was unaffected by the use of an antibody against syndecan-1. However, this event was abolished by an antibody against RANKL. These results, not necessarily conflicting, could be in relation with the expression level of the receptors in the two cellular models. In this context, an internalization process was put forward. Confocal microscopy demonstrated via the clathrin pathway an internalization of OPG mediated by RANKL. After being internalized, OPG was then degraded by the proteasome and the lysosome. A similar internalization phenomenon was also observed in osteoblast cells expressing physiologically RANKL, thus validating our data observed on 293RL cells. Western blotting analysis revealed that the half-life of RANKL was greatly reduced in the presence of OPG, pointing out that OPG binding to RANKL induces an enhancement of the ligand internalization. By the light of these results, the inhibitory effect of OPG on bone resorption can be explained not only by a decoy receptor function, competitor inhibitor of the RANK/RANKL binding, but also by the modulation of the RANKL half-life induced by OPG. Reciprocally, this modulation contributes to reduce the bioavailability of OPG.

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Authors
Tat, S. K., Padrines, M., Theoleyre, S., Couillaud-Battaglia, S., Heymann, D., Redini, F., & Fortun, Y.
Affiliations
Inserm (FR)
Corresponding author
Fortun, Yannick
ORCID
Heymann, Dominique
Venue
Bone
Publisher
Elsevier BV
Published
2006-10
Volume
39
Issue
4
Pages
706-715
ISSN
  • 1873-2763 (ISSN-L)
  • 8756-3282
DOI
10.1016/j.bone.2006.03.016
OpenAlex
W1988444499
Cited by
63
References
53
Citations by year
2025: 2 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 2 · 2018: 3 · 2017: 4 · 2016: 3 · 2015: 3 · 2014: 1 · 2013: 4 · 2012: 4
FWCI
2.58
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Bone (publishedVersion)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
osteoprotegerin, RANKL, receptor internalization, clathrin-mediated endocytosis, proteasomal degradation, lysosomal degradation, osteoblasts, bone resorption, osteolytic bone disease, syndecan-1
MeSH terms
Acetylcysteine, Animals, Antibodies, Cell Line, Cells, Cultured, Chloroquine, Clathrin, Enzyme-Linked Immunosorbent Assay, Heparin, Humans, Lysosomes, Osteoclasts, Protein Binding, Blotting, Western, Signal Transduction, Cysteine Proteinase Inhibitors, Microscopy, Confocal, Reverse Transcriptase Polymerase Chain Reaction, Proteasome Endopeptidase Complex, Mice, Osteoprotegerin, RANK Ligand, Syndecans, Proteasome Inhibitors

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