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Inducible Wnt16 inactivation: WNT16 regulates cortical bone thickness in adult mice.

Journal article
Authors Claes Ohlsson
Petra Henning
Karin H. Nilsson
Jianyao Wu
Karin L. Gustafsson
Klara Sjögren
Anna E Törnqvist
Antti Koskela
Fu-Ping Zhang
Marie Lagerquist
Matti Poutanen
Juha Tuukkanen
Ulf H Lerner
Sofia Movérare-Skrtic
Published in The Journal of endocrinology
Volume 237
Issue 2
Pages 113-122
ISSN 1479-6805
Publication year 2018
Published at Centre for Bone and Arthritis Research
Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
Pages 113-122
Language en
Links dx.doi.org/10.1530/JOE-18-0020
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Endocrinology

Abstract

Substantial progress has been made in the therapeutic reduction of vertebral fracture risk in patients with osteoporosis, but non-vertebral fracture risk has been improved only marginally. Human genetic studies demonstrate that the WNT16 locus is a major determinant of cortical bone thickness and non-vertebral fracture risk and mouse models with life-long Wnt16 inactivation revealed that WNT16 is a key regulator of cortical thickness. These studies, however, could not exclude that the effect of Wnt16 inactivation on cortical thickness might be caused by early developmental and/or growth effects. To determine the effect of WNT16 specifically on adult cortical bone homeostasis, Wnt16 was conditionally ablated in young adult and old mice through tamoxifen-inducible Cre-mediated recombination using CAG-Cre-ER; Wnt16flox/flox (Cre-Wnt16flox/flox) mice. First, 10-week-old Cre-Wnt16flox/flox and Wnt16flox/flox littermate control mice were treated with tamoxifen. Four weeks later, Wnt16 mRNA levels in cortical bone were reduced and cortical thickness in femur was decreased in Cre-Wnt16flox/flox mice compared to Wnt16flox/flox mice. Then, inactivation of Wnt16 in 47-week-old mice (evaluated four weeks later) resulted in a reduction of Wnt16 mRNA levels, cortical thickness and cortical bone strength with no effect on trabecular bone volume fraction. Mechanistic studies demonstrated that the reduced cortical bone thickness was caused by a combination of increased bone resorption and reduced periosteal bone formation. In conclusion, WNT16 is a crucial regulator of cortical bone thickness in young adult and old mice. We propose that new treatment strategies targeting the adult regulation of WNT16 might be useful to reduce fracture risk at cortical bone sites.

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