Document Detail

Protein isoprenylation regulates osteogenic differentiation of mesenchymal stem cells: effect of alendronate, and farnesyl and geranylgeranyl transferase inhibitors.
MedLine Citation:
PMID:  21077849     Owner:  NLM     Status:  MEDLINE    
BACKGROUND AND PURPOSE: Protein isoprenylation is an important step in the intracellular signalling pathway conducting cell growth and differentiation. In bone, protein isoprenylation is required for osteoclast differentiation and activation. However, its role in osteoblast differentiation and function remains unknown. In this study, we assessed the role of protein isoprenylation in osteoblastogenesis in a model of mesenchymal stem cells (MSC) differentiation.
EXPERIMENTAL APPROACH: We tested the effect of an inhibitor of farnesylation [farnesyl transferase inhibitor-277 (FTI-277)] and one of geranylgeranylation [geranylgeranyltransferase inhibitor-298 (GGTI-298)] on osteoblast differentiating MSC. In addition, we tested the effect of alendronate on protein isoprenylation in this model either alone or in combination with other inhibitors of isoprenylation.
KEY RESULTS: Initially, we found that levels of unfarnesylated proteins (prelamin A and HDJ-2) increased after treatment with FTI-277 concomitantly affecting osteoblastogenesis and increasing nuclear morphological changes without affecting cell survival. Furthermore, inhibition of geranylgeranylation by GGTI-298 alone increased osteoblastogenesis. This effect was enhanced by the combination of GGTI-298 and alendronate in the osteogenic media.
CONCLUSIONS AND IMPLICATIONS: Our data indicate that both farnesylation and geranylgeranylation play a role in osteoblastogenesis. In addition, a new mechanism of action for alendronate on protein isoprenylation in osteogenic differentiating MSC in vitro was found. In conclusion, protein isoprenylation is an important component of the osteoblast differentiation process that could constitute a new therapeutic target for osteoporosis in the future.
G Duque; C Vidal; D Rivas
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  162     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-01-28     Completed Date:  2011-05-06     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1109-18     Citation Subset:  IM    
Copyright Information:
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
Ageing Bone Research Program, Sydney Medical School - Nepean Campus, The University of Sydney, Penrith, NSW, Australia.
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MeSH Terms
Alendronate / pharmacology*
Alkyl and Aryl Transferases / antagonists & inhibitors
Benzamides / pharmacology
Bone Density Conservation Agents / pharmacology
Cell Differentiation / drug effects*,  physiology
Cell Nucleus / drug effects
Enzyme Inhibitors / pharmacology
Farnesyltranstransferase / antagonists & inhibitors
Mesenchymal Stromal Cells / cytology,  drug effects*,  metabolism*
Methionine / analogs & derivatives,  pharmacology
Osteoblasts / cytology,  drug effects,  metabolism
Osteogenesis / drug effects*,  physiology
Protein Prenylation / drug effects
Grant Support
//Canadian Institutes of Health Research
Reg. No./Substance:
0/Benzamides; 0/Bone Density Conservation Agents; 0/Enzyme Inhibitors; 0/FTI 277; 0/GGTI 298; 63-68-3/Methionine; 66376-36-1/Alendronate; EC 2.5.-/Alkyl and Aryl Transferases; EC 2.5.1.-/geranylgeranyltransferase type-I; EC

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