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PTH-Induced Bone Regeneration and Vascular Modulation Are Both Dependent on Endothelial Signaling
The use of a bone allograft presents a promising approach for healing nonunion fractures. We have previously reported that parathyroid hormone (PTH) therapy induced allograft integration while modulating angiogenesis at the allograft proximity. Here, we hypothesize that PTH-induced vascular modulati...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8909576/ https://www.ncbi.nlm.nih.gov/pubmed/35269519 http://dx.doi.org/10.3390/cells11050897 |
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author | Cohn-Schwartz, Doron Schary, Yeshai Yalon, Eran Krut, Zoe Da, Xiaoyu Schwarz, Edward M. Gazit, Dan Pelled, Gadi Gazit, Zulma |
author_facet | Cohn-Schwartz, Doron Schary, Yeshai Yalon, Eran Krut, Zoe Da, Xiaoyu Schwarz, Edward M. Gazit, Dan Pelled, Gadi Gazit, Zulma |
author_sort | Cohn-Schwartz, Doron |
collection | PubMed |
description | The use of a bone allograft presents a promising approach for healing nonunion fractures. We have previously reported that parathyroid hormone (PTH) therapy induced allograft integration while modulating angiogenesis at the allograft proximity. Here, we hypothesize that PTH-induced vascular modulation and the osteogenic effect of PTH are both dependent on endothelial PTH receptor-1 (PTHR1) signaling. To evaluate our hypothesis, we used multiple transgenic mouse lines, and their wild-type counterparts as a control. In addition to endothelial-specific PTHR1 knock-out mice, we used mice in which PTHR1 was engineered to be constitutively active in collagen-1α+ osteoblasts, to assess the effect of PTH signaling activation exclusively in osteoprogenitors. To characterize resident cell recruitment and osteogenic activity, mice in which the Luciferase reporter gene is expressed under the Osteocalcin promoter (Oc-Luc) were used. Mice were implanted with calvarial allografts and treated with either PTH or PBS. A micro-computed tomography-based structural analysis indicated that the induction of bone formation by PTH, as observed in wild-type animals, was not maintained when PTHR1 was removed from endothelial cells. Furthermore, the induction of PTH signaling exclusively in osteoblasts resulted in significantly less bone formation compared to systemic PTH treatment, and significantly less osteogenic activity was measured by bioluminescence imaging of the Oc-Luc mice. Deletion of the endothelial PTHR1 significantly decreased the PTH-induced formation of narrow blood vessels, formerly demonstrated in wild-type mice. However, the exclusive activation of PTH signaling in osteoblasts was sufficient to re-establish the observed PTH effect. Collectively, our results show that endothelial PTHR1 signaling plays a key role in PTH-induced osteogenesis and has implications in angiogenesis. |
format | Online Article Text |
id | pubmed-8909576 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-89095762022-03-11 PTH-Induced Bone Regeneration and Vascular Modulation Are Both Dependent on Endothelial Signaling Cohn-Schwartz, Doron Schary, Yeshai Yalon, Eran Krut, Zoe Da, Xiaoyu Schwarz, Edward M. Gazit, Dan Pelled, Gadi Gazit, Zulma Cells Article The use of a bone allograft presents a promising approach for healing nonunion fractures. We have previously reported that parathyroid hormone (PTH) therapy induced allograft integration while modulating angiogenesis at the allograft proximity. Here, we hypothesize that PTH-induced vascular modulation and the osteogenic effect of PTH are both dependent on endothelial PTH receptor-1 (PTHR1) signaling. To evaluate our hypothesis, we used multiple transgenic mouse lines, and their wild-type counterparts as a control. In addition to endothelial-specific PTHR1 knock-out mice, we used mice in which PTHR1 was engineered to be constitutively active in collagen-1α+ osteoblasts, to assess the effect of PTH signaling activation exclusively in osteoprogenitors. To characterize resident cell recruitment and osteogenic activity, mice in which the Luciferase reporter gene is expressed under the Osteocalcin promoter (Oc-Luc) were used. Mice were implanted with calvarial allografts and treated with either PTH or PBS. A micro-computed tomography-based structural analysis indicated that the induction of bone formation by PTH, as observed in wild-type animals, was not maintained when PTHR1 was removed from endothelial cells. Furthermore, the induction of PTH signaling exclusively in osteoblasts resulted in significantly less bone formation compared to systemic PTH treatment, and significantly less osteogenic activity was measured by bioluminescence imaging of the Oc-Luc mice. Deletion of the endothelial PTHR1 significantly decreased the PTH-induced formation of narrow blood vessels, formerly demonstrated in wild-type mice. However, the exclusive activation of PTH signaling in osteoblasts was sufficient to re-establish the observed PTH effect. Collectively, our results show that endothelial PTHR1 signaling plays a key role in PTH-induced osteogenesis and has implications in angiogenesis. MDPI 2022-03-05 /pmc/articles/PMC8909576/ /pubmed/35269519 http://dx.doi.org/10.3390/cells11050897 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Cohn-Schwartz, Doron Schary, Yeshai Yalon, Eran Krut, Zoe Da, Xiaoyu Schwarz, Edward M. Gazit, Dan Pelled, Gadi Gazit, Zulma PTH-Induced Bone Regeneration and Vascular Modulation Are Both Dependent on Endothelial Signaling |
title | PTH-Induced Bone Regeneration and Vascular Modulation Are Both Dependent on Endothelial Signaling |
title_full | PTH-Induced Bone Regeneration and Vascular Modulation Are Both Dependent on Endothelial Signaling |
title_fullStr | PTH-Induced Bone Regeneration and Vascular Modulation Are Both Dependent on Endothelial Signaling |
title_full_unstemmed | PTH-Induced Bone Regeneration and Vascular Modulation Are Both Dependent on Endothelial Signaling |
title_short | PTH-Induced Bone Regeneration and Vascular Modulation Are Both Dependent on Endothelial Signaling |
title_sort | pth-induced bone regeneration and vascular modulation are both dependent on endothelial signaling |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8909576/ https://www.ncbi.nlm.nih.gov/pubmed/35269519 http://dx.doi.org/10.3390/cells11050897 |
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