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Asparaginase Potentiates Glucocorticoid-Induced Osteonecrosis in a Mouse Model

Osteonecrosis is a common dose-limiting toxicity of glucocorticoids. Data from clinical trials suggest that other medications can increase the risk of glucocorticoid-induced osteonecrosis. Here we utilized a mouse model to study the effect of asparaginase treatment on dexamethasone-induced osteonecr...

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Autores principales: Liu, Chengcheng, Janke, Laura J., Kawedia, Jitesh D., Ramsey, Laura B., Cai, Xiangjun, Mattano, Leonard A., Boyd, Kelli L., Funk, Amy J., Relling, Mary V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788417/
https://www.ncbi.nlm.nih.gov/pubmed/26967741
http://dx.doi.org/10.1371/journal.pone.0151433
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author Liu, Chengcheng
Janke, Laura J.
Kawedia, Jitesh D.
Ramsey, Laura B.
Cai, Xiangjun
Mattano, Leonard A.
Boyd, Kelli L.
Funk, Amy J.
Relling, Mary V.
author_facet Liu, Chengcheng
Janke, Laura J.
Kawedia, Jitesh D.
Ramsey, Laura B.
Cai, Xiangjun
Mattano, Leonard A.
Boyd, Kelli L.
Funk, Amy J.
Relling, Mary V.
author_sort Liu, Chengcheng
collection PubMed
description Osteonecrosis is a common dose-limiting toxicity of glucocorticoids. Data from clinical trials suggest that other medications can increase the risk of glucocorticoid-induced osteonecrosis. Here we utilized a mouse model to study the effect of asparaginase treatment on dexamethasone-induced osteonecrosis. Mice receiving asparaginase along with dexamethasone had a higher rate of osteonecrosis than those receiving only dexamethasone after 6 weeks of treatment (44% vs. 10%, P = 0.006). Similarly, epiphyseal arteriopathy, which we have shown to be an initiating event for osteonecrosis, was observed in 58% of mice receiving asparaginase and dexamethasone compared to 17% of mice receiving dexamethasone only (P = 0.007). As in the clinic, greater exposure to asparaginase was associated with greater plasma exposure to dexamethasone (P = 0.0001). This model also recapitulated other clinical risk factors for osteonecrosis, including age at start of treatment, and association with the systemic exposure to dexamethasone (P = 0.027) and asparaginase (P = 0.036). We conclude that asparaginase can potentiate the osteonecrotic effect of glucocorticoids.
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spelling pubmed-47884172016-03-23 Asparaginase Potentiates Glucocorticoid-Induced Osteonecrosis in a Mouse Model Liu, Chengcheng Janke, Laura J. Kawedia, Jitesh D. Ramsey, Laura B. Cai, Xiangjun Mattano, Leonard A. Boyd, Kelli L. Funk, Amy J. Relling, Mary V. PLoS One Research Article Osteonecrosis is a common dose-limiting toxicity of glucocorticoids. Data from clinical trials suggest that other medications can increase the risk of glucocorticoid-induced osteonecrosis. Here we utilized a mouse model to study the effect of asparaginase treatment on dexamethasone-induced osteonecrosis. Mice receiving asparaginase along with dexamethasone had a higher rate of osteonecrosis than those receiving only dexamethasone after 6 weeks of treatment (44% vs. 10%, P = 0.006). Similarly, epiphyseal arteriopathy, which we have shown to be an initiating event for osteonecrosis, was observed in 58% of mice receiving asparaginase and dexamethasone compared to 17% of mice receiving dexamethasone only (P = 0.007). As in the clinic, greater exposure to asparaginase was associated with greater plasma exposure to dexamethasone (P = 0.0001). This model also recapitulated other clinical risk factors for osteonecrosis, including age at start of treatment, and association with the systemic exposure to dexamethasone (P = 0.027) and asparaginase (P = 0.036). We conclude that asparaginase can potentiate the osteonecrotic effect of glucocorticoids. Public Library of Science 2016-03-11 /pmc/articles/PMC4788417/ /pubmed/26967741 http://dx.doi.org/10.1371/journal.pone.0151433 Text en © 2016 Liu et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Liu, Chengcheng
Janke, Laura J.
Kawedia, Jitesh D.
Ramsey, Laura B.
Cai, Xiangjun
Mattano, Leonard A.
Boyd, Kelli L.
Funk, Amy J.
Relling, Mary V.
Asparaginase Potentiates Glucocorticoid-Induced Osteonecrosis in a Mouse Model
title Asparaginase Potentiates Glucocorticoid-Induced Osteonecrosis in a Mouse Model
title_full Asparaginase Potentiates Glucocorticoid-Induced Osteonecrosis in a Mouse Model
title_fullStr Asparaginase Potentiates Glucocorticoid-Induced Osteonecrosis in a Mouse Model
title_full_unstemmed Asparaginase Potentiates Glucocorticoid-Induced Osteonecrosis in a Mouse Model
title_short Asparaginase Potentiates Glucocorticoid-Induced Osteonecrosis in a Mouse Model
title_sort asparaginase potentiates glucocorticoid-induced osteonecrosis in a mouse model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788417/
https://www.ncbi.nlm.nih.gov/pubmed/26967741
http://dx.doi.org/10.1371/journal.pone.0151433
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