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Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy
Dysregulated Wnt signaling is associated with the pathogenesis of cancers, fibrosis, and vascular diseases. Inhibition of Wnt signaling has shown efficacy in various pre-clinical models of these disorders. One of the key challenges in developing targeted anti-cancer drugs is to balance efficacy with...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968037/ https://www.ncbi.nlm.nih.gov/pubmed/29844946 http://dx.doi.org/10.1038/s41413-018-0017-8 |
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author | Madan, Babita McDonald, Mitchell J. Foxa, Gabrielle E. Diegel, Cassandra R. Williams, Bart O. Virshup, David M. |
author_facet | Madan, Babita McDonald, Mitchell J. Foxa, Gabrielle E. Diegel, Cassandra R. Williams, Bart O. Virshup, David M. |
author_sort | Madan, Babita |
collection | PubMed |
description | Dysregulated Wnt signaling is associated with the pathogenesis of cancers, fibrosis, and vascular diseases. Inhibition of Wnt signaling has shown efficacy in various pre-clinical models of these disorders. One of the key challenges in developing targeted anti-cancer drugs is to balance efficacy with on-target toxicity. Given the crucial role Wnts play in the differentiation of osteoblasts and osteoclasts, acute inhibition of Wnt signaling is likely to affect bone homeostasis. In this study, we evaluated the skeletal effect of small molecule inhibitor of an o-acyl transferase porcupine (PORCN) that prevents Wnt signaling by blocking the secretion of all Wnts. Micro-computed tomography and histomorphometric evaluation revealed that the bones of mice treated with two structurally distinct PORCN inhibitors LGK974 and ETC-1922159 (ETC-159) had loss-of-bone volume and density within 4 weeks of exposure. This decreased bone mass was associated with a significant increase in adipocytes within the bone marrow. Notably, simultaneous administration of a clinically approved anti-resorptive, alendronate, a member of the bisphosphonate family, mitigated loss-of-bone mass seen upon ETC-159 treatment by regulating activity of osteoclasts and blocking accumulation of bone marrow adipocytes. Our results support the addition of bone protective agents when treating patients with PORCN inhibitors. Mitigation of bone toxicity can extend the therapeutic utility of Wnt pathway inhibitors. |
format | Online Article Text |
id | pubmed-5968037 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-59680372018-05-29 Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy Madan, Babita McDonald, Mitchell J. Foxa, Gabrielle E. Diegel, Cassandra R. Williams, Bart O. Virshup, David M. Bone Res Article Dysregulated Wnt signaling is associated with the pathogenesis of cancers, fibrosis, and vascular diseases. Inhibition of Wnt signaling has shown efficacy in various pre-clinical models of these disorders. One of the key challenges in developing targeted anti-cancer drugs is to balance efficacy with on-target toxicity. Given the crucial role Wnts play in the differentiation of osteoblasts and osteoclasts, acute inhibition of Wnt signaling is likely to affect bone homeostasis. In this study, we evaluated the skeletal effect of small molecule inhibitor of an o-acyl transferase porcupine (PORCN) that prevents Wnt signaling by blocking the secretion of all Wnts. Micro-computed tomography and histomorphometric evaluation revealed that the bones of mice treated with two structurally distinct PORCN inhibitors LGK974 and ETC-1922159 (ETC-159) had loss-of-bone volume and density within 4 weeks of exposure. This decreased bone mass was associated with a significant increase in adipocytes within the bone marrow. Notably, simultaneous administration of a clinically approved anti-resorptive, alendronate, a member of the bisphosphonate family, mitigated loss-of-bone mass seen upon ETC-159 treatment by regulating activity of osteoclasts and blocking accumulation of bone marrow adipocytes. Our results support the addition of bone protective agents when treating patients with PORCN inhibitors. Mitigation of bone toxicity can extend the therapeutic utility of Wnt pathway inhibitors. Nature Publishing Group UK 2018-05-25 /pmc/articles/PMC5968037/ /pubmed/29844946 http://dx.doi.org/10.1038/s41413-018-0017-8 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Madan, Babita McDonald, Mitchell J. Foxa, Gabrielle E. Diegel, Cassandra R. Williams, Bart O. Virshup, David M. Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy |
title | Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy |
title_full | Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy |
title_fullStr | Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy |
title_full_unstemmed | Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy |
title_short | Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy |
title_sort | bone loss from wnt inhibition mitigated by concurrent alendronate therapy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968037/ https://www.ncbi.nlm.nih.gov/pubmed/29844946 http://dx.doi.org/10.1038/s41413-018-0017-8 |
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