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Prevention of glucocorticoid-associated osteonecrosis by intravenous administration of mesenchymal stem cells in a rabbit model

BACKGROUND: Glucocorticoid-associated osteonecrosis is an intractable condition, making the establishment of preventative strategies of particular importance. Recently various studies using mesenchymal stem cells (MSC) have been conducted. Using a rabbit glucocorticoid-associated osteonecrosis model...

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Autores principales: Ueda, Shusuke, Shimasaki, Miyako, Ichiseki, Toru, Ueda, Yoshimichi, Tsuchiya, Masanobu, Kaneuji, Ayumi, Kawahara, Norio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698964/
https://www.ncbi.nlm.nih.gov/pubmed/29162088
http://dx.doi.org/10.1186/s12891-017-1837-1
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author Ueda, Shusuke
Shimasaki, Miyako
Ichiseki, Toru
Ueda, Yoshimichi
Tsuchiya, Masanobu
Kaneuji, Ayumi
Kawahara, Norio
author_facet Ueda, Shusuke
Shimasaki, Miyako
Ichiseki, Toru
Ueda, Yoshimichi
Tsuchiya, Masanobu
Kaneuji, Ayumi
Kawahara, Norio
author_sort Ueda, Shusuke
collection PubMed
description BACKGROUND: Glucocorticoid-associated osteonecrosis is an intractable condition, making the establishment of preventative strategies of particular importance. Recently various studies using mesenchymal stem cells (MSC) have been conducted. Using a rabbit glucocorticoid-associated osteonecrosis model we administered green fluorescent protein (GFP)-labeled MSC intravenously to investigate their effect on osteonecrosis. METHODS: A rabbit osteonecrosis model in which methylprednisolone (MP) 20 mg/kg was injected into the gluteus of a Japanese white rabbit was used. Simultaneously with MP, MSC labeled with GFP (GFP-labeled MSC) were injected intravenously. Fourteen days later the animals were killed (MSC(+)/MP(+)/14d), femurs were extracted, and the prevalence of osteonecrosis was determined histopathologically. Also, animals were killed 3 days after simultaneous administration of GFP-labeled MSC and MP (MSC(+)/MP(+)/3d), and western blotting (WB) for GFP was performed of the femur, liver, kidney, lung, blood vessel, and vertebra, in addition to immunohistochemical study of femur. As a control for the histopathological study, animals were killed 14 days after MP administration and intravenous vehicle injection (MSC(−)/MP(+)/14d). For WB, animals were killed 3 days after intravenous GFP-labeled MSC administration and vehicle injection into the gluteus (MSC(+)/MP(−)/3d). RESULTS: In MSC(−)/MP(+)/14d osteonecrosis was found in 7 of 10 rabbits (70%), while in MSC(+)/MP(+)/14d, partial bone marrow necrosis was found in only 1 rabbit (12.5%); osteonecrosis was not found in 7 of 8 rabbits (p < 0.05). WB showed expression of GFP in the femur, not in the liver, kidney, lung, blood vessel, or vertebra, of MSC(+)/MP(+)/3d; expression of GFP-labeled MSC was absent in the femur of MSC(+)/MP(−)/3d. In the immunohistochemical study of MSC(+)/MP(+)/3d, homing of GFP-labeled MSC was noted perivascularly in the femur, but not in MSC(+)/MP(−)/3d. CONCLUSIONS: With transvenous MSC administration a significant prophylactic effect against glucocorticoid-associated osteonecrosis was found. Direct administration of MSC to the site of tissue injury requires highly invasive surgery. In contrast, as shown here the simple and hardly invasive intravenous administration of MSC may succeed in preventing osteonecrosis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12891-017-1837-1) contains supplementary material, which is available to authorized users.
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spelling pubmed-56989642017-12-01 Prevention of glucocorticoid-associated osteonecrosis by intravenous administration of mesenchymal stem cells in a rabbit model Ueda, Shusuke Shimasaki, Miyako Ichiseki, Toru Ueda, Yoshimichi Tsuchiya, Masanobu Kaneuji, Ayumi Kawahara, Norio BMC Musculoskelet Disord Research Article BACKGROUND: Glucocorticoid-associated osteonecrosis is an intractable condition, making the establishment of preventative strategies of particular importance. Recently various studies using mesenchymal stem cells (MSC) have been conducted. Using a rabbit glucocorticoid-associated osteonecrosis model we administered green fluorescent protein (GFP)-labeled MSC intravenously to investigate their effect on osteonecrosis. METHODS: A rabbit osteonecrosis model in which methylprednisolone (MP) 20 mg/kg was injected into the gluteus of a Japanese white rabbit was used. Simultaneously with MP, MSC labeled with GFP (GFP-labeled MSC) were injected intravenously. Fourteen days later the animals were killed (MSC(+)/MP(+)/14d), femurs were extracted, and the prevalence of osteonecrosis was determined histopathologically. Also, animals were killed 3 days after simultaneous administration of GFP-labeled MSC and MP (MSC(+)/MP(+)/3d), and western blotting (WB) for GFP was performed of the femur, liver, kidney, lung, blood vessel, and vertebra, in addition to immunohistochemical study of femur. As a control for the histopathological study, animals were killed 14 days after MP administration and intravenous vehicle injection (MSC(−)/MP(+)/14d). For WB, animals were killed 3 days after intravenous GFP-labeled MSC administration and vehicle injection into the gluteus (MSC(+)/MP(−)/3d). RESULTS: In MSC(−)/MP(+)/14d osteonecrosis was found in 7 of 10 rabbits (70%), while in MSC(+)/MP(+)/14d, partial bone marrow necrosis was found in only 1 rabbit (12.5%); osteonecrosis was not found in 7 of 8 rabbits (p < 0.05). WB showed expression of GFP in the femur, not in the liver, kidney, lung, blood vessel, or vertebra, of MSC(+)/MP(+)/3d; expression of GFP-labeled MSC was absent in the femur of MSC(+)/MP(−)/3d. In the immunohistochemical study of MSC(+)/MP(+)/3d, homing of GFP-labeled MSC was noted perivascularly in the femur, but not in MSC(+)/MP(−)/3d. CONCLUSIONS: With transvenous MSC administration a significant prophylactic effect against glucocorticoid-associated osteonecrosis was found. Direct administration of MSC to the site of tissue injury requires highly invasive surgery. In contrast, as shown here the simple and hardly invasive intravenous administration of MSC may succeed in preventing osteonecrosis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12891-017-1837-1) contains supplementary material, which is available to authorized users. BioMed Central 2017-11-21 /pmc/articles/PMC5698964/ /pubmed/29162088 http://dx.doi.org/10.1186/s12891-017-1837-1 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Ueda, Shusuke
Shimasaki, Miyako
Ichiseki, Toru
Ueda, Yoshimichi
Tsuchiya, Masanobu
Kaneuji, Ayumi
Kawahara, Norio
Prevention of glucocorticoid-associated osteonecrosis by intravenous administration of mesenchymal stem cells in a rabbit model
title Prevention of glucocorticoid-associated osteonecrosis by intravenous administration of mesenchymal stem cells in a rabbit model
title_full Prevention of glucocorticoid-associated osteonecrosis by intravenous administration of mesenchymal stem cells in a rabbit model
title_fullStr Prevention of glucocorticoid-associated osteonecrosis by intravenous administration of mesenchymal stem cells in a rabbit model
title_full_unstemmed Prevention of glucocorticoid-associated osteonecrosis by intravenous administration of mesenchymal stem cells in a rabbit model
title_short Prevention of glucocorticoid-associated osteonecrosis by intravenous administration of mesenchymal stem cells in a rabbit model
title_sort prevention of glucocorticoid-associated osteonecrosis by intravenous administration of mesenchymal stem cells in a rabbit model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698964/
https://www.ncbi.nlm.nih.gov/pubmed/29162088
http://dx.doi.org/10.1186/s12891-017-1837-1
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