Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41413-018-0017-8
Title: Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy
Authors: Madan, B 
McDonald, M.J
Foxa, G.E
Diegel, C.R
Williams, B.O
Virshup, D.M 
Keywords: alendronic acid
osteocalcin
osteoprotegerin
sclerostin
Wnt protein
adipocyte
animal experiment
animal model
animal tissue
Article
bone density
bone marrow
bone mass
bone structure
controlled study
cortical thickness (bone)
male
micro-computed tomography
morphometry
mouse
nonhuman
osteoblast
osteoclast
osteolysis
porcupine
Wnt signaling
Issue Date: 2018
Publisher: Springer Nature
Citation: Madan, B, McDonald, M.J, Foxa, G.E, Diegel, C.R, Williams, B.O, Virshup, D.M (2018). Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy. Bone Research 6 (1) : 17. ScholarBank@NUS Repository. https://doi.org/10.1038/s41413-018-0017-8
Rights: Attribution 4.0 International
Abstract: 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. © 2018 The Author(s).
Source Title: Bone Research
URI: https://scholarbank.nus.edu.sg/handle/10635/183825
ISSN: 2095-4700
DOI: 10.1038/s41413-018-0017-8
Rights: Attribution 4.0 International
Appears in Collections:Staff Publications
Elements

Show full item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
10_1038_s41413-018-0017-8.pdf3.32 MBAdobe PDF

OPEN

NoneView/Download

SCOPUSTM   
Citations

23
checked on Apr 15, 2021

Page view(s)

35
checked on Apr 15, 2021

Google ScholarTM

Check

Altmetric


This item is licensed under a Creative Commons License Creative Commons