Abstract
Thiazolidinediones (TZDs) represent an interesting treatment of type 2 diabetes mellitus. However, adverse effects such as heart problems and bone fractures have already been reported. Previously, we reported that pioglitazone and rosiglitazone induce osteocyte apoptosis and sclerostin up-regulation; however, the molecular mechanisms leading to such effects are unknown. In this study, we found that TZDs rapidly activated Erk1/2 and p38. These activations were mediated through Ras proteins and GPR40, a receptor expressed on the surface of osteocytes. Activation of this pathway led only to osteocyte apoptosis but not sclerostin up-regulation. On the other hand, TZDs were capable of activating peroxisome proliferator-activated receptor-γ, and activation of this signaling pathway led to sclerostin up-regulation but not osteocyte apoptosis. This study demonstrates two distinct signaling pathways activated in osteocytes in response to TZDs that could participate in the observed increase in fractures in TZD-treated patients.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Apoptosis / drug effects*
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Blotting, Western
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Cell Line
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Cells, Cultured
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Female
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Glycoproteins / metabolism
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Intercellular Signaling Peptides and Proteins
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Mice
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Microscopy, Electron, Transmission
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Osteoblasts / drug effects
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Osteoblasts / metabolism
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Osteocytes / drug effects*
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Osteocytes / metabolism
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Osteocytes / ultrastructure
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PPAR gamma / genetics
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PPAR gamma / metabolism
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Phosphorylation / drug effects
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RNA Interference
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Reactive Oxygen Species / metabolism
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / metabolism*
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Signal Transduction / drug effects
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Thiazolidinediones / pharmacology*
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Up-Regulation / drug effects
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p38 Mitogen-Activated Protein Kinases / metabolism
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ras Proteins / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Ffar1 protein, mouse
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Glycoproteins
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Intercellular Signaling Peptides and Proteins
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PPAR gamma
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Reactive Oxygen Species
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Receptors, G-Protein-Coupled
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Sost protein, mouse
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Thiazolidinediones
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases
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ras Proteins