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.
MeSH terms
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Acid Phosphatase / metabolism
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Actins / metabolism
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Adaptor Proteins, Signal Transducing
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Alendronate / pharmacology
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Alkyl and Aryl Transferases / antagonists & inhibitors
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Animals
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Apoptosis / drug effects
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Blotting, Western
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Bone Marrow Cells / cytology
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Bone Marrow Cells / metabolism
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Bone Resorption / metabolism
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Bone Resorption / pathology
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Carrier Proteins / metabolism
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Carrier Proteins / pharmacology
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Carrier Proteins / physiology
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Caspase 3
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Caspase 9
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Caspases / metabolism
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Cell Cycle Proteins
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Cell Survival / drug effects
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Collagen / metabolism
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Collagen Type I
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Cytokines / pharmacology
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Cytokines / physiology*
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Diterpenes / pharmacology
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Enzyme Inhibitors / pharmacology
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Eukaryotic Initiation Factors
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Immunohistochemistry
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Interleukin-1 / pharmacology
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Isoenzymes / metabolism
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Macrophage Colony-Stimulating Factor / pharmacology
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Macrophage Colony-Stimulating Factor / physiology
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Membrane Glycoproteins / pharmacology
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Membrane Glycoproteins / physiology
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Mice
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Models, Biological
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NF-kappa B / analysis
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NF-kappa B / metabolism
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Osteoclasts / cytology
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Osteoclasts / drug effects
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Osteoclasts / physiology*
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Peptides / metabolism
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Phosphoproteins / metabolism
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Protein Kinases / physiology*
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Protein Serine-Threonine Kinases / metabolism
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Protein Synthesis Inhibitors / pharmacology
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Proto-Oncogene Proteins / analysis
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Ribosomal Protein S6 / metabolism
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism*
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Serine-Threonine Kinase 3
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Signal Transduction / physiology
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases
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Tartrate-Resistant Acid Phosphatase
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Tumor Necrosis Factor-alpha / pharmacology
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Tumor Necrosis Factor-alpha / physiology
Substances
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Actins
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Cell Cycle Proteins
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Collagen Type I
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Cytokines
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Diterpenes
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Eif4ebp1 protein, mouse
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Enzyme Inhibitors
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Eukaryotic Initiation Factors
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Interleukin-1
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Isoenzymes
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Membrane Glycoproteins
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NF-kappa B
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Peptides
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Phosphoproteins
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Protein Synthesis Inhibitors
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Proto-Oncogene Proteins
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Ribosomal Protein S6
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Tnfrsf11a protein, mouse
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Tnfsf11 protein, mouse
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Tumor Necrosis Factor-alpha
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collagen type I trimeric cross-linked peptide
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Macrophage Colony-Stimulating Factor
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Collagen
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geranylgeraniol
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Alkyl and Aryl Transferases
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geranylgeranyltransferase type-I
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Protein Kinases
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Stk4 protein, mouse
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mTOR protein, mouse
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Ribosomal Protein S6 Kinases, 70-kDa
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Serine-Threonine Kinase 3
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Stk3 protein, mouse
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TOR Serine-Threonine Kinases
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Acid Phosphatase
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Tartrate-Resistant Acid Phosphatase
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Casp3 protein, mouse
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Casp9 protein, mouse
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Caspase 3
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Caspase 9
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Caspases
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Sirolimus
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Alendronate