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Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice

Journal article
Authors Thomas Funck-Brentano
Karin H. Nilsson
Robert Brommage
Petra Henning
Ulf H Lerner
A. Koskela
J. Tuukkanen
M. Cohen-Solal
Sofia Moverare-Skrtic
Claes Ohlsson
Published in Journal of Endocrinology
Volume 238
Issue 1
Pages 13-23
ISSN 0022-0795
Publication year 2018
Published at Centre for Bone and Arthritis Research
Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
Pages 13-23
Language en
Links dx.doi.org/10.1530/joe-18-0153
Keywords Wnt signaling pathway, targeted therapy, osteoporosis, animal models, focal dermal hypoplasia, postmenopausal women, beta-catenin, wnt, cancer, osteoporosis, romosozumab, disease, osteoblasts, progenitor, Endocrinology & Metabolism, ates of america, v109, pe2197, naka h, 1990, international orthopaedics, v14, p179, ates of america, v112, p14972
Subject categories Endocrinology and Diabetes

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, mu CT 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.

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