Cargando…

Effects of oral losartan administration on homeostasis of articular cartilage and bone in a rabbit model

BACKGROUND AND AIMS: Previous work has shown that oral losartan can enhance microfracture-mediated cartilage repair in a rabbit osteochondral defect injury model. In this study, we aimed to determine whether oral losartan would have a detrimental effect on articular cartilage and bone homeostasis in...

Descripción completa

Detalles Bibliográficos
Autores principales: Deng, Zhenhan, Gao, Xueqin, Utsunomiya, Hajime, Arner, Justin W., Ruzbarsky, Joseph J., Huard, Matthieu, Ravuri, Sudheer, Philippon, Marc J., Huard, Johnny
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8971351/
https://www.ncbi.nlm.nih.gov/pubmed/35372645
http://dx.doi.org/10.1016/j.bonr.2022.101526
_version_ 1784679613219209216
author Deng, Zhenhan
Gao, Xueqin
Utsunomiya, Hajime
Arner, Justin W.
Ruzbarsky, Joseph J.
Huard, Matthieu
Ravuri, Sudheer
Philippon, Marc J.
Huard, Johnny
author_facet Deng, Zhenhan
Gao, Xueqin
Utsunomiya, Hajime
Arner, Justin W.
Ruzbarsky, Joseph J.
Huard, Matthieu
Ravuri, Sudheer
Philippon, Marc J.
Huard, Johnny
author_sort Deng, Zhenhan
collection PubMed
description BACKGROUND AND AIMS: Previous work has shown that oral losartan can enhance microfracture-mediated cartilage repair in a rabbit osteochondral defect injury model. In this study, we aimed to determine whether oral losartan would have a detrimental effect on articular cartilage and bone homeostasis in the uninjured sides. METHODS: New Zealand rabbits were divided into 4 groups including normal uninjured (Normal), contralateral uninjured side of osteochondral defect (Defect), osteochondral defect plus microfracture (Microfracture) and osteochondral defect plus microfracture and losartan oral administration (10 mg/kg/day) (Losartan). Rabbits underwent different surgeries and treatment and were sacrificed at 12 weeks. Both side of the normal group and uninjured side of treatment groups tibias were harvested for Micro-CT and histological analysis for cartilage and bone including H&E staining, Herovici's staining (bone and cartilage) Alcian blue and Safranin O staining (cartilage) as well as immunohistochemistry of losartan related signaling pathways molecules for both cartilage and bone. RESULTS: Our results showed losartan oral treatment at 10 mg/kg/day slightly increase Alcian blue positive matrix as well as decrease collagen type 3 in articular cartilage while having no significant effect on articular cartilage structure, cellularity, and other matrix. Losartan treatment also did not affect angiotensin receptor type 1 (AGTR1), angiotensin receptor type 2 (AGTR2) and phosphorylated transforming factor β1 activated kinase 1 (pTAK1) expression level and pattern in the articular cartilage. Furthermore, losartan treatment did not affect microarchitecture of normal cancellous bone and cortical bone of tibias compared to normal and other groups. Losartan treatment slightly increased osteocalcin positive osteoblasts on the surface of cancellous bone and did not affect bone matrix collagen type 1 content and did not change AGTR1, AGTR2 and pTAK1 signal molecule expression. CONCLUSION: Oral losartan used as a microfracture augmentation therapeutic does not have significant effect on uninjured articular cartilage and bone based on our preclinical rabbit model. These results provided further evidence that the current regimen of using losartan as a microfracture augmentation therapeutic is safe with respect to bone and cartilage homeostasis and support clinical trials for its application in human cartilage repair.
format Online
Article
Text
id pubmed-8971351
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-89713512022-04-02 Effects of oral losartan administration on homeostasis of articular cartilage and bone in a rabbit model Deng, Zhenhan Gao, Xueqin Utsunomiya, Hajime Arner, Justin W. Ruzbarsky, Joseph J. Huard, Matthieu Ravuri, Sudheer Philippon, Marc J. Huard, Johnny Bone Rep Full Length Article BACKGROUND AND AIMS: Previous work has shown that oral losartan can enhance microfracture-mediated cartilage repair in a rabbit osteochondral defect injury model. In this study, we aimed to determine whether oral losartan would have a detrimental effect on articular cartilage and bone homeostasis in the uninjured sides. METHODS: New Zealand rabbits were divided into 4 groups including normal uninjured (Normal), contralateral uninjured side of osteochondral defect (Defect), osteochondral defect plus microfracture (Microfracture) and osteochondral defect plus microfracture and losartan oral administration (10 mg/kg/day) (Losartan). Rabbits underwent different surgeries and treatment and were sacrificed at 12 weeks. Both side of the normal group and uninjured side of treatment groups tibias were harvested for Micro-CT and histological analysis for cartilage and bone including H&E staining, Herovici's staining (bone and cartilage) Alcian blue and Safranin O staining (cartilage) as well as immunohistochemistry of losartan related signaling pathways molecules for both cartilage and bone. RESULTS: Our results showed losartan oral treatment at 10 mg/kg/day slightly increase Alcian blue positive matrix as well as decrease collagen type 3 in articular cartilage while having no significant effect on articular cartilage structure, cellularity, and other matrix. Losartan treatment also did not affect angiotensin receptor type 1 (AGTR1), angiotensin receptor type 2 (AGTR2) and phosphorylated transforming factor β1 activated kinase 1 (pTAK1) expression level and pattern in the articular cartilage. Furthermore, losartan treatment did not affect microarchitecture of normal cancellous bone and cortical bone of tibias compared to normal and other groups. Losartan treatment slightly increased osteocalcin positive osteoblasts on the surface of cancellous bone and did not affect bone matrix collagen type 1 content and did not change AGTR1, AGTR2 and pTAK1 signal molecule expression. CONCLUSION: Oral losartan used as a microfracture augmentation therapeutic does not have significant effect on uninjured articular cartilage and bone based on our preclinical rabbit model. These results provided further evidence that the current regimen of using losartan as a microfracture augmentation therapeutic is safe with respect to bone and cartilage homeostasis and support clinical trials for its application in human cartilage repair. Elsevier 2022-03-28 /pmc/articles/PMC8971351/ /pubmed/35372645 http://dx.doi.org/10.1016/j.bonr.2022.101526 Text en © 2022 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Full Length Article
Deng, Zhenhan
Gao, Xueqin
Utsunomiya, Hajime
Arner, Justin W.
Ruzbarsky, Joseph J.
Huard, Matthieu
Ravuri, Sudheer
Philippon, Marc J.
Huard, Johnny
Effects of oral losartan administration on homeostasis of articular cartilage and bone in a rabbit model
title Effects of oral losartan administration on homeostasis of articular cartilage and bone in a rabbit model
title_full Effects of oral losartan administration on homeostasis of articular cartilage and bone in a rabbit model
title_fullStr Effects of oral losartan administration on homeostasis of articular cartilage and bone in a rabbit model
title_full_unstemmed Effects of oral losartan administration on homeostasis of articular cartilage and bone in a rabbit model
title_short Effects of oral losartan administration on homeostasis of articular cartilage and bone in a rabbit model
title_sort effects of oral losartan administration on homeostasis of articular cartilage and bone in a rabbit model
topic Full Length Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8971351/
https://www.ncbi.nlm.nih.gov/pubmed/35372645
http://dx.doi.org/10.1016/j.bonr.2022.101526
work_keys_str_mv AT dengzhenhan effectsoforallosartanadministrationonhomeostasisofarticularcartilageandboneinarabbitmodel
AT gaoxueqin effectsoforallosartanadministrationonhomeostasisofarticularcartilageandboneinarabbitmodel
AT utsunomiyahajime effectsoforallosartanadministrationonhomeostasisofarticularcartilageandboneinarabbitmodel
AT arnerjustinw effectsoforallosartanadministrationonhomeostasisofarticularcartilageandboneinarabbitmodel
AT ruzbarskyjosephj effectsoforallosartanadministrationonhomeostasisofarticularcartilageandboneinarabbitmodel
AT huardmatthieu effectsoforallosartanadministrationonhomeostasisofarticularcartilageandboneinarabbitmodel
AT ravurisudheer effectsoforallosartanadministrationonhomeostasisofarticularcartilageandboneinarabbitmodel
AT philipponmarcj effectsoforallosartanadministrationonhomeostasisofarticularcartilageandboneinarabbitmodel
AT huardjohnny effectsoforallosartanadministrationonhomeostasisofarticularcartilageandboneinarabbitmodel