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The bone-sparing effects of estrogen and WNT16 are independent of each other

Journal article
Authors Sofia Movérare-Skrtic
Jianyao Wu
Petra Henning
Karin L. Gustafsson
Klara Sjögren
Sara H Windahl
A. Koskela
J. Tuukkanen
Anna E Börjesson
Marie K Lagerquist
Ulf H Lerner
F.P. Zhang
J.Å. Gustafsson
Matti Poutanen
Claes Ohlsson
Published in Proceedings of the National Academy of Sciences of the United States of America
Volume 112
Issue 48
Pages 14972-14977
ISSN 0027-8424
Publication year 2015
Published at Centre for Bone and Arthritis Research
Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
Pages 14972-14977
Language en
Links dx.doi.org/10.1073/pnas.1520408112
Keywords Cortical bone , Estrogen , Trabecular bone , Transgenic mice , WNT16
Subject categories Physiology, Endocrinology

Abstract

Wingless-type MMTV integration site family (WNT)16 is a key regulator of bone mass with high expression in cortical bone, and Wnt16-/- mice have reduced cortical bone mass. As Wnt16 expression is enhanced by estradiol treatment, we hypothesized that the bone-sparing effect of estrogen in females isWNT16-dependent. This hypothesis was tested in mechanistic studies using two genetically modified mouse models with either constantly high osteoblastic Wnt16 expression or no Wnt16 expression. We developed a mouse model with osteoblast-specific Wnt16 overexpression (Obl-Wnt16). These mice had several-fold elevated Wnt16 expression in both trabecular and cortical bone compared with wild type (WT) mice. Obl- Wnt16 mice displayed increased total body bone mineral density (BMD), surprisingly caused mainly by a substantial increase in trabecular bone mass, resulting in improved bone strength of vertebrae L3. Ovariectomy (ovx) reduced the total body BMD and the trabecular bone mass to the same degree in Obl-Wnt16 mice and WT mice, suggesting that the bone-sparing effect of estrogen is WNT16-independent. However, these bone parameters were similar in ovx Obl- Wnt16 mice and sham operated WT mice. The role of WNT16 for the bone-sparing effect of estrogen was also evaluated in Wnt16-/- mice. Treatment with estradiol increased the trabecular and cortical bone mass to a similar extent in both Wnt16-/- and WT mice. In conclusion, the bone-sparing effects of estrogen and WNT16 are independent of each other. Furthermore, loss of endogenous WNT16 results specifically in cortical bone loss, whereas overexpression of WNT16 surprisingly increases mainly trabecular bone mass. WNT16- targeted therapies might be useful for treatment of postmenopausal trabecular bone loss.

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