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Alendronate Inhibits VEGF Expression in Growth Plate Chondrocytes by Acting on the Mevalonate Pathway

Bisphosphonates decrease chondrocyte turnover at the growth plate and impact bone growth. Likewise vascular endothelial growth factor (VEGF) plays an important role in endochondral bone elongation by influencing chondrocyte turnover at the growth plate. To investigate whether the action of bisphosph...

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Autores principales: Evans, K.D, Oberbauer, A.M
Formato: Texto
Lenguaje:English
Publicado: Bentham Open 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2761671/
https://www.ncbi.nlm.nih.gov/pubmed/19834579
http://dx.doi.org/10.2174/1874325000903010083
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author Evans, K.D
Oberbauer, A.M
author_facet Evans, K.D
Oberbauer, A.M
author_sort Evans, K.D
collection PubMed
description Bisphosphonates decrease chondrocyte turnover at the growth plate and impact bone growth. Likewise vascular endothelial growth factor (VEGF) plays an important role in endochondral bone elongation by influencing chondrocyte turnover at the growth plate. To investigate whether the action of bisphosphonate on the growth plate works through VEGF, VEGF protein expression and isoform transcription in endochondral chondrocytes isolated from growing mice and treated with a clinically used bisphosphonate, alendronate, were assessed. Alendronate at 10µM and 100µM concentrations decreased secreted VEGF protein expression but not cell associated protein. Bisphosphonates are known to inhibit the mevalonate intracellular signaling pathway used by VEGF. Addition of the mevalonate pathway intermediates farnesol (FOH) and geranylgeraniol (GGOH) interacted with the low concentration of alendronate to further decrease secreted VEGF protein whereas FOH partially restored VEGF protein secretion when combined with the high alendronate. Similar to the protein data, the addition of alendronate decreased VEGF mRNA isoforms. VEGF mRNA levels were rescued by the GGOH mevalonate pathway intermediate at the low alendronate dose whereas neither intermediate consistently restored the VEGF mRNA levels at the high alendronate dose. Thus, the bisphophonate alendronate impairs growth plate chondrocyte turnover by down-regulating the secreted forms of VEGF mRNA and protein by inhibiting the mevalonate pathway.
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spelling pubmed-27616712009-10-15 Alendronate Inhibits VEGF Expression in Growth Plate Chondrocytes by Acting on the Mevalonate Pathway Evans, K.D Oberbauer, A.M Open Orthop J Article Bisphosphonates decrease chondrocyte turnover at the growth plate and impact bone growth. Likewise vascular endothelial growth factor (VEGF) plays an important role in endochondral bone elongation by influencing chondrocyte turnover at the growth plate. To investigate whether the action of bisphosphonate on the growth plate works through VEGF, VEGF protein expression and isoform transcription in endochondral chondrocytes isolated from growing mice and treated with a clinically used bisphosphonate, alendronate, were assessed. Alendronate at 10µM and 100µM concentrations decreased secreted VEGF protein expression but not cell associated protein. Bisphosphonates are known to inhibit the mevalonate intracellular signaling pathway used by VEGF. Addition of the mevalonate pathway intermediates farnesol (FOH) and geranylgeraniol (GGOH) interacted with the low concentration of alendronate to further decrease secreted VEGF protein whereas FOH partially restored VEGF protein secretion when combined with the high alendronate. Similar to the protein data, the addition of alendronate decreased VEGF mRNA isoforms. VEGF mRNA levels were rescued by the GGOH mevalonate pathway intermediate at the low alendronate dose whereas neither intermediate consistently restored the VEGF mRNA levels at the high alendronate dose. Thus, the bisphophonate alendronate impairs growth plate chondrocyte turnover by down-regulating the secreted forms of VEGF mRNA and protein by inhibiting the mevalonate pathway. Bentham Open 2009-10-01 /pmc/articles/PMC2761671/ /pubmed/19834579 http://dx.doi.org/10.2174/1874325000903010083 Text en © Evans and Oberbauer; Licensee Bentham Open. http://creativecommons.org/licenses/by-nc/3.0/ This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.
spellingShingle Article
Evans, K.D
Oberbauer, A.M
Alendronate Inhibits VEGF Expression in Growth Plate Chondrocytes by Acting on the Mevalonate Pathway
title Alendronate Inhibits VEGF Expression in Growth Plate Chondrocytes by Acting on the Mevalonate Pathway
title_full Alendronate Inhibits VEGF Expression in Growth Plate Chondrocytes by Acting on the Mevalonate Pathway
title_fullStr Alendronate Inhibits VEGF Expression in Growth Plate Chondrocytes by Acting on the Mevalonate Pathway
title_full_unstemmed Alendronate Inhibits VEGF Expression in Growth Plate Chondrocytes by Acting on the Mevalonate Pathway
title_short Alendronate Inhibits VEGF Expression in Growth Plate Chondrocytes by Acting on the Mevalonate Pathway
title_sort alendronate inhibits vegf expression in growth plate chondrocytes by acting on the mevalonate pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2761671/
https://www.ncbi.nlm.nih.gov/pubmed/19834579
http://dx.doi.org/10.2174/1874325000903010083
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