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The Rho GTPase RAC1 in Osteoblasts Controls Their Function

The regulation of the differentiation of the bone-forming cells, the osteoblasts, is complex. Many signaling pathways converge on the master regulator of osteoblast differentiation Runx2. The role of molecules that integrate several signaling pathways such as the Rho GTPases need to be better unders...

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Autores principales: Huck, Katrin, Sens, Carla, Wuerfel, Carina, Zoeller, Caren, A. Nakchbandi, Inaam
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014472/
https://www.ncbi.nlm.nih.gov/pubmed/31936261
http://dx.doi.org/10.3390/ijms21020385
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author Huck, Katrin
Sens, Carla
Wuerfel, Carina
Zoeller, Caren
A. Nakchbandi, Inaam
author_facet Huck, Katrin
Sens, Carla
Wuerfel, Carina
Zoeller, Caren
A. Nakchbandi, Inaam
author_sort Huck, Katrin
collection PubMed
description The regulation of the differentiation of the bone-forming cells, the osteoblasts, is complex. Many signaling pathways converge on the master regulator of osteoblast differentiation Runx2. The role of molecules that integrate several signaling pathways such as the Rho GTPases need to be better understood. We, therefore, asked at which stage Rac1, one of the Rho GTPase, is needed for osteoblast differentiation and whether it is involved in two pathways, the anabolic response to parathyroid hormone and the stimulatory effect of fibronectin isoforms on integrins. Genetic deletion of Rac1 in preosteoblasts using the osterix promoter diminished osteoblast differentiation in vitro. This effect was however similar to the presence of the promoter by itself. We, therefore, applied a Rac1 inhibitor and confirmed a decrease in differentiation. In vivo, Rac1 deletion using the osterix promoter decreased bone mineral density as well as histomorphometric measures of osteoblast function. In contrast, deleting Rac1 in differentiating osteoblasts using the collagen α1(I) promoter had no effects. We then evaluated whether intermittent parathyroid hormone (PTH) was able to affect bone mineral density in the absence of Rac1 in preosteoblasts. The increase in bone mineral density was similar in control animals and in mice in which Rac1 was deleted using the osterix promoter. Furthermore, stimulation of integrin by integrin isoforms was able to enhance osteoblast differentiation, despite the deletion of Rac1. In summary, Rac1 in preosteoblasts is required for normal osteoblast function and bone density, but it is neither needed for PTH-mediated anabolic effects nor for integrin-mediated enhancement of differentiation.
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spelling pubmed-70144722020-03-09 The Rho GTPase RAC1 in Osteoblasts Controls Their Function Huck, Katrin Sens, Carla Wuerfel, Carina Zoeller, Caren A. Nakchbandi, Inaam Int J Mol Sci Article The regulation of the differentiation of the bone-forming cells, the osteoblasts, is complex. Many signaling pathways converge on the master regulator of osteoblast differentiation Runx2. The role of molecules that integrate several signaling pathways such as the Rho GTPases need to be better understood. We, therefore, asked at which stage Rac1, one of the Rho GTPase, is needed for osteoblast differentiation and whether it is involved in two pathways, the anabolic response to parathyroid hormone and the stimulatory effect of fibronectin isoforms on integrins. Genetic deletion of Rac1 in preosteoblasts using the osterix promoter diminished osteoblast differentiation in vitro. This effect was however similar to the presence of the promoter by itself. We, therefore, applied a Rac1 inhibitor and confirmed a decrease in differentiation. In vivo, Rac1 deletion using the osterix promoter decreased bone mineral density as well as histomorphometric measures of osteoblast function. In contrast, deleting Rac1 in differentiating osteoblasts using the collagen α1(I) promoter had no effects. We then evaluated whether intermittent parathyroid hormone (PTH) was able to affect bone mineral density in the absence of Rac1 in preosteoblasts. The increase in bone mineral density was similar in control animals and in mice in which Rac1 was deleted using the osterix promoter. Furthermore, stimulation of integrin by integrin isoforms was able to enhance osteoblast differentiation, despite the deletion of Rac1. In summary, Rac1 in preosteoblasts is required for normal osteoblast function and bone density, but it is neither needed for PTH-mediated anabolic effects nor for integrin-mediated enhancement of differentiation. MDPI 2020-01-08 /pmc/articles/PMC7014472/ /pubmed/31936261 http://dx.doi.org/10.3390/ijms21020385 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Huck, Katrin
Sens, Carla
Wuerfel, Carina
Zoeller, Caren
A. Nakchbandi, Inaam
The Rho GTPase RAC1 in Osteoblasts Controls Their Function
title The Rho GTPase RAC1 in Osteoblasts Controls Their Function
title_full The Rho GTPase RAC1 in Osteoblasts Controls Their Function
title_fullStr The Rho GTPase RAC1 in Osteoblasts Controls Their Function
title_full_unstemmed The Rho GTPase RAC1 in Osteoblasts Controls Their Function
title_short The Rho GTPase RAC1 in Osteoblasts Controls Their Function
title_sort rho gtpase rac1 in osteoblasts controls their function
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014472/
https://www.ncbi.nlm.nih.gov/pubmed/31936261
http://dx.doi.org/10.3390/ijms21020385
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