Document Detail

Thiazolidinediones induce osteocyte apoptosis by a G protein-coupled receptor 40-dependent mechanism.
MedLine Citation:
PMID:  22593579     Owner:  NLM     Status:  MEDLINE    
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.
Aleksandra Mieczkowska; Michel F Baslé; Daniel Chappard; Guillaume Mabilleau
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Publication Detail:
Type:  Journal Article     Date:  2012-05-16
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-09     Completed Date:  2012-10-09     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  23517-26     Citation Subset:  IM    
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, United Kingdom.
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MeSH Terms
Apoptosis / drug effects*
Blotting, Western
Cell Line
Cells, Cultured
Glycoproteins / metabolism
Microscopy, Electron, Transmission
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Osteoblasts / drug effects,  metabolism
Osteocytes / drug effects*,  metabolism,  ultrastructure
PPAR gamma / genetics,  metabolism
Phosphorylation / drug effects
RNA Interference
Reactive Oxygen Species / metabolism
Receptors, G-Protein-Coupled / genetics,  metabolism*
Signal Transduction / drug effects
Thiazolidinediones / pharmacology*
Up-Regulation / drug effects
p38 Mitogen-Activated Protein Kinases / metabolism
ras Proteins / metabolism
Reg. No./Substance:
0/Glycoproteins; 0/Gpr40 protein, mouse; 0/PPAR gamma; 0/Reactive Oxygen Species; 0/Receptors, G-Protein-Coupled; 0/Sost protein, mouse; 0/Thiazolidinediones; EC Protein Kinase 1; EC Protein Kinase 3; EC Mitogen-Activated Protein Kinases; EC Proteins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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