Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy

Babita Madan,Cassandra R Diegel,David M Virshup,Gabrielle E Foxa,Bart O Williams,Mitchell J Mcdonald

doi:10.1038/s41413-018-0017-8

Babita Madan, Cassandra R Diegel + Show 4 more

Open Access

https://doi.org/10.1038/s41413-018-0017-8

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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.

Highlights

Wnt signaling plays key roles in many aspects of development and adult tissue homeostasis.[1,2] WNTs are secreted palmitoleated glycoprotein ligands that bind to cell surface receptors to initiate signaling in diverse tissues and cell types
Dynamic histomorphometric analysis of cortical bone (Fig. 4e) showed a significant decrease in cortical area fraction (CAF) and RESULTS Exposure to PORCN inhibitors results in significant bone loss To analyze the effect of Wnt secretion inhibitors on bone homeostasis, 8-week-old female mice were treated with two structurally distinct PORCN inhibitors, ETC-159 and LGK974.10,12
None of the treatments caused a significant change in endocorand the trabecular and cortical regions of the left femurs were tical mineral apposition rate (MAR) or BFR (Fig. 4i, j)

Summary

Introduction

Wnt signaling plays key roles in many aspects of development and adult tissue homeostasis.[1,2] WNTs are secreted palmitoleated glycoprotein ligands that bind to cell surface receptors to initiate signaling in diverse tissues and cell types. The secretion of all Wnts can be blocked by inhibition of PORCN. PORCN is an endoplasmic reticulum resident O-acyl transferase that catalyzes the palmitoleation of all Wnts.[2,9] Preclinical studies of PORCN inhibitors have demonstrated robust activity against several tumor types. Available drugs that inhibit PORCN have been developed and have progressed to human clinical trials.[6,10,11,12,13] concerns regarding mechanism-based toxicity of Wnt pathway inhibitors could impact the clinical utility of these agents

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