Abstract

WNT signaling is involved in the tumorigenesis of various cancers and regulates bone homeostasis. Palmitoleoylation of WNTs by Porcupine is required for WNT activity. Porcupine inhibitors are under development for cancer therapy. As the possible side effects of Porcupine inhibitors on bone health are unknown, we determined their effects on bone mass and strength. Twelve-week-old C57BL/6N female mice were treated by the Porcupine inhibitors LGK974 (low dose = 3 mg/kg/day; high dose = 6 mg/kg/day) or Wnt-C59 (10 mg/kg/day) or vehicle for 3 weeks. Bone parameters were assessed by serum biomarkers, dual-energy X-ray absorptiometry, µCT and histomorphometry. Bone strength was measured by the 3-point bending test. The Porcupine inhibitors were well tolerated demonstrated by normal body weight. Both doses of LGK974 and Wnt-C59 reduced total body bone mineral density compared with vehicle treatment (P < 0.001). Cortical thickness of the femur shaft (P < 0.001) and trabecular bone volume fraction in the vertebral body (P < 0.001) were reduced by treatment with LGK974 or Wnt-C59. Porcupine inhibition reduced bone strength in the tibia (P < 0.05). The cortical bone loss was the result of impaired periosteal bone formation and increased endocortical bone resorption and the trabecular bone loss was caused by reduced trabecular bone formation and increased bone resorption. Porcupine inhibitors exert deleterious effects on bone mass and strength caused by a combination of reduced bone formation and increased bone resorption. We suggest that cancer targeted therapies using Porcupine inhibitors may increase the risk of fractures.

Highlights

  • WNT ligands belong to a family of 19 secreted cysteinerich glycoproteins that are essential for development and tissue homeostasis (Clevers & Nusse 2012)

  • Porcn expression was compared in cortical diaphyseal bone, vertebral body, fat and liver (Fig. 1A)

  • Porcn was expressed in all tissues, but the mRNA levels were higher in cortical bone compared to vertebral body

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Summary

Introduction

WNT ligands belong to a family of 19 secreted cysteinerich glycoproteins that are essential for development and tissue homeostasis (Clevers & Nusse 2012). They signal through both the canonical WNT-β-catenin pathway and the noncanonical pathways (Moon et al 2002, Kohn & Moon 2005). The first demonstration of the link between WNT and cancer was that aberrant overexpression of WNT1 caused spontaneous mammary hyperplasia and retrovirusinduced mammary tumors in mice (Nusse & Varmus 1982)

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