University of Oulu

Funck-Brentano, T., Nilsson, K. H., Brommage, R., Henning, P., Lerner, U. H., Koskela, A., … Ohlsson, C. (2018). Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice. Journal of Endocrinology, 238(1), 13–23. https://doi.org/10.1530/joe-18-0153

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

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Author: Funck-Brentano, Thomas1; Nilsson, Karin H.1; Brommage, Robert1;
Organizations: 1Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
2Unit of Cancer Research and Translational Medicine, MRC Oulu and Department of Anatomy and Cell Biology, University of Oulu, Oulu, Finland
3BIOSCAR UMRS 1132, Université Paris Diderot, Sorbonne Paris Cité, INSERM, Paris, France
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.4 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2019100130682
Language: English
Published: Bioscientifica, 2018
Publish Date: 2019-10-01
Description:

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.

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Series: Journal of endocrinology
ISSN: 0022-0795
ISSN-E: 1479-6805
ISSN-L: 0022-0795
Volume: 238
Issue: 1
Pages: 13 - 23
DOI: 10.1530/JOE-18-0153
OADOI: https://oadoi.org/10.1530/JOE-18-0153
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Subjects:
Funding: This work was supported by funding from the European Union’s Horizon 2020 Marie Skłodowska-Curie Actions research and innovation programme under grant agreement GOTBONE-750579, the French Society of Rheumatology, Vinnova, the Swedish Research Council, the Swedish Foundation for Strategic Research, the ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Knut and Alice Wallenberg Foundation, the Torsten Söderberg Foundation, and the Novo Nordisk Foundation.
Copyright information: © 2018 The authors. Published by Bioscientifica Ltd. This work is licensed under a Creative Commons Attribution 4.0 Unported License.
  https://creativecommons.org/licenses/by/4.0/