Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy.

Autor:	Madan B; 1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, 169857 Singapore., McDonald MJ; 2Center for Cancer and Cell Biology and Program for Skeletal Disease and Tumor Microenvironment, Van Andel Research Institute, Grand Rapids, MI 49503 USA., Foxa GE; 2Center for Cancer and Cell Biology and Program for Skeletal Disease and Tumor Microenvironment, Van Andel Research Institute, Grand Rapids, MI 49503 USA., Diegel CR; 2Center for Cancer and Cell Biology and Program for Skeletal Disease and Tumor Microenvironment, Van Andel Research Institute, Grand Rapids, MI 49503 USA., Williams BO; 2Center for Cancer and Cell Biology and Program for Skeletal Disease and Tumor Microenvironment, Van Andel Research Institute, Grand Rapids, MI 49503 USA., Virshup DM; 1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, 169857 Singapore.; 3Department of Pediatrics, Duke University, Durham, NC USA.
Jazyk:	angličtina
Zdroj:	Bone research [Bone Res] 2018 May 25; Vol. 6, pp. 17. Date of Electronic Publication: 2018 May 25 (Print Publication: 2018).
DOI:	10.1038/s41413-018-0017-8
Abstrakt:	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. Competing Interests: B.M. and D.M.V. are co-inventors of a small molecule PORCN inhibitor.
Databáze:	MEDLINE
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