M-CSF, TNFα and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase

Glantschnig, H; Fisher, J E; Wesolowski, G; Rodan, G A; Reszka, A A

doi:10.1038/sj.cdd.4401285

Cited by 350Bone Metabolism and DiseasesPI3K/AKT/mTOR signaling in cancerRheumatoid Arthritis Research and Therapies

M-CSF, TNFα and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase

Glantschnig, H, Fisher, J E, Wesolowski, G, Rodan, G A, Reszka, A A·2003·Cell Death & Differentiation

DOI 10.1038/sj.cdd.4401285

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Abstract

Multinucleated bone-resorbing osteoclasts (Ocl) are cells of hematopoietic origin that play a major role in osteoporosis pathophysiology. Ocl survival and activity require M-CSF and RANK ligand (RANKL). M-CSF signals to Akt, while RANKL, like TNFalpha, activates NF-kappaB. We show here that although these are separate pathways in the Ocl, signaling of all three cytokines converges on mammalian target of rapamycin (mTOR) as part of their antiapoptotic action. Accordingly, rapamycin blocks M-CSF- and RANKL-dependent Ocl survival inducing apoptosis, and suppresses in vitro bone resorption proportional to the reduction in Ocl number. The cytokine signaling intermediates for mTOR/ribosomal protein S6 kinase (S6K) activation include phosphatidylinositol-3 kinase, Akt, Erks and geranylgeranylated proteins. Inhibitors of these intermediates suppress cytokine activation of S6K and induce Ocl apoptosis. mTOR regulates protein translation acting via S6K, 4E-BP1 and S6. We find that inhibition of translation by other mechanisms also induces Ocl apoptosis, demonstrating that Ocl survival is highly sensitive to continuous de novo protein synthesis. This study thus identifies mTOR/S6K as an essential signaling pathway engaged in the stimulation of cell survival in osteoclasts.

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Ito, S., Ohmi, A., Sakamiya, A. K., Yano, T., Okumura, K., Nishimura, N., & Kagontani, K. (2016) · Bioscience Biotechnology and Biochemistry · doi:10.1080/09168451.2015.1127133 · Cited by 19 · see citing works
RANKL as the master regulator of osteoclast differentiation
Takayanagi, H. (2021) · Journal of Bone and Mineral Metabolism · doi:10.1007/s00774-020-01191-1 · Cited by 175 · see citing works

Authors: Glantschnig, H., Fisher, J. E., Wesolowski, G., Rodan, G. A., & Reszka, A. A.
Affiliations: Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Corresponding author: Reszka, A A
ORCID: Fisher, J E
Venue: Cell Death & Differentiation
Publisher: Springer Science and Business Media LLC
Published: 2003-09-19
Volume: 10
Issue: 10
Pages: 1165-1177
ISSN: 1350-9047 (ISSN-L)
1476-5403
DOI: 10.1038/sj.cdd.4401285
OpenAlex: W1560301770
Cited by: 350
References: 64
Citations by year: 2026: 6 · 2025: 16 · 2024: 11 · 2023: 9 · 2022: 15 · 2021: 15 · 2020: 19 · 2019: 18 · 2018: 21 · 2017: 13 · 2016: 18 · 2015: 20 · 2014: 23 · 2013: 14 · 2012: 13
FWCI: 4.37
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Cell Death and Differentiation (publishedVersion)
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 › PI3K/AKT/mTOR signaling in cancer
Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
Keywords: osteoclasts, osteoclast survival, mTOR, S6 kinase, macrophage colony-stimulating factor, RANK ligand, TNF-α, apoptosis, bone resorption, osteoporosis, Akt signaling, NF-κB, phosphatidylinositol 3-kinase, mRNA translation, 4E-BP1, rapamycin
MeSH terms: Tartrate-Resistant Acid Phosphatase, Serine-Threonine Kinase 3, Hippo Kinases, Acid Phosphatase, Actins, Animals, Bone Marrow Cells, Bone Resorption, Carrier Proteins, Cell Survival, Collagen, Diterpenes, Enzyme Inhibitors, Immunohistochemistry, Interleukin-1, Isoenzymes, Membrane Glycoproteins, Models, Biological, Osteoclasts, Peptides, Phosphoproteins, Protein Kinases, Protein Synthesis Inhibitors, Proto-Oncogene Proteins, Tumor Necrosis Factor-alpha, Blotting, Western, Signal Transduction, Macrophage Colony-Stimulating Factor, Cytokines, NF-kappa B, Apoptosis, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Alendronate, Alkyl and Aryl Transferases, Sirolimus, Caspases, Collagen Type I, Ribosomal Protein S6, Ribosomal Protein S6 Kinases, 70-kDa, Eukaryotic Initiation Factors, Adaptor Proteins, Signal Transducing, Proto-Oncogene Proteins c-akt, Mice, Caspase 3, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B, Caspase 9, TOR Serine-Threonine Kinases

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M-CSF, TNFα and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase

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