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Sost Haploinsufficiency Provokes Peracute Lethal Cardiac Tamponade without Rescuing the Osteopenia in a Mouse Model of Excess Glucocorticoids
Glucocorticoid-induced secondary osteoporosis is the most predictable side effect of this anti-inflammatory. One of the main mechanisms by which glucocorticoids achieve such deleterious outcome in bone is by antagonizing Wnt/β-catenin signaling. Sclerostin, encoded by Sost gene, is the main negative...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Investigative Pathology
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445804/ https://www.ncbi.nlm.nih.gov/pubmed/30664862 http://dx.doi.org/10.1016/j.ajpath.2018.12.007 |
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author | Javaheri, Behzad Herbert, Eleanor Hopkinson, Mark Al-Jazzar, Ahmed Pitsillides, Andrew A. |
author_facet | Javaheri, Behzad Herbert, Eleanor Hopkinson, Mark Al-Jazzar, Ahmed Pitsillides, Andrew A. |
author_sort | Javaheri, Behzad |
collection | PubMed |
description | Glucocorticoid-induced secondary osteoporosis is the most predictable side effect of this anti-inflammatory. One of the main mechanisms by which glucocorticoids achieve such deleterious outcome in bone is by antagonizing Wnt/β-catenin signaling. Sclerostin, encoded by Sost gene, is the main negative regulator of the proformative and antiresorptive role of the Wnt signaling pathway in the skeleton. It was hypothesized that the partial inactivation of sclerostin function by genetic manipulation will rescue the osteopenia induced by high endogenous glucocorticoid levels. Sost-deficient mice were crossed with an established mouse model of excess glucocorticoids, and the effects on bone mass and structure were evaluated. Sost haploinsufficiency did not rescue the low bone mass induced by high glucocorticoids. Intriguingly, the critical manifestation of Sost deficiency combined with glucocorticoid excess was sporadic, sudden, unprovoked, and nonconvulsive death. Detailed histopathologic analysis in a wide range of tissues identified peracute hemopericardium and cardiac tamponade to be the cause. These preclinical studies reveal outcomes with direct relevance to ongoing clinical trials that explore the use of antisclerostin antibodies as a treatment for osteoporosis. They particularly highlight a potential for increased cardiovascular risk and may inform improved stratification of patients who might otherwise benefit from antisclerostin antibody treatment. |
format | Online Article Text |
id | pubmed-6445804 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | American Society for Investigative Pathology |
record_format | MEDLINE/PubMed |
spelling | pubmed-64458042019-04-12 Sost Haploinsufficiency Provokes Peracute Lethal Cardiac Tamponade without Rescuing the Osteopenia in a Mouse Model of Excess Glucocorticoids Javaheri, Behzad Herbert, Eleanor Hopkinson, Mark Al-Jazzar, Ahmed Pitsillides, Andrew A. Am J Pathol Article Glucocorticoid-induced secondary osteoporosis is the most predictable side effect of this anti-inflammatory. One of the main mechanisms by which glucocorticoids achieve such deleterious outcome in bone is by antagonizing Wnt/β-catenin signaling. Sclerostin, encoded by Sost gene, is the main negative regulator of the proformative and antiresorptive role of the Wnt signaling pathway in the skeleton. It was hypothesized that the partial inactivation of sclerostin function by genetic manipulation will rescue the osteopenia induced by high endogenous glucocorticoid levels. Sost-deficient mice were crossed with an established mouse model of excess glucocorticoids, and the effects on bone mass and structure were evaluated. Sost haploinsufficiency did not rescue the low bone mass induced by high glucocorticoids. Intriguingly, the critical manifestation of Sost deficiency combined with glucocorticoid excess was sporadic, sudden, unprovoked, and nonconvulsive death. Detailed histopathologic analysis in a wide range of tissues identified peracute hemopericardium and cardiac tamponade to be the cause. These preclinical studies reveal outcomes with direct relevance to ongoing clinical trials that explore the use of antisclerostin antibodies as a treatment for osteoporosis. They particularly highlight a potential for increased cardiovascular risk and may inform improved stratification of patients who might otherwise benefit from antisclerostin antibody treatment. American Society for Investigative Pathology 2019-04 /pmc/articles/PMC6445804/ /pubmed/30664862 http://dx.doi.org/10.1016/j.ajpath.2018.12.007 Text en © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. http://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 | Article Javaheri, Behzad Herbert, Eleanor Hopkinson, Mark Al-Jazzar, Ahmed Pitsillides, Andrew A. Sost Haploinsufficiency Provokes Peracute Lethal Cardiac Tamponade without Rescuing the Osteopenia in a Mouse Model of Excess Glucocorticoids |
title | Sost Haploinsufficiency Provokes Peracute Lethal Cardiac Tamponade without Rescuing the Osteopenia in a Mouse Model of Excess Glucocorticoids |
title_full | Sost Haploinsufficiency Provokes Peracute Lethal Cardiac Tamponade without Rescuing the Osteopenia in a Mouse Model of Excess Glucocorticoids |
title_fullStr | Sost Haploinsufficiency Provokes Peracute Lethal Cardiac Tamponade without Rescuing the Osteopenia in a Mouse Model of Excess Glucocorticoids |
title_full_unstemmed | Sost Haploinsufficiency Provokes Peracute Lethal Cardiac Tamponade without Rescuing the Osteopenia in a Mouse Model of Excess Glucocorticoids |
title_short | Sost Haploinsufficiency Provokes Peracute Lethal Cardiac Tamponade without Rescuing the Osteopenia in a Mouse Model of Excess Glucocorticoids |
title_sort | sost haploinsufficiency provokes peracute lethal cardiac tamponade without rescuing the osteopenia in a mouse model of excess glucocorticoids |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445804/ https://www.ncbi.nlm.nih.gov/pubmed/30664862 http://dx.doi.org/10.1016/j.ajpath.2018.12.007 |
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