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

Sofia Movérare-Skrtic, Jianyao Wu, Petra Henning, Karin L. Gustafsson, Klara Sjögren, Sara H. Windahl, Antti Koskela, Juha Tuukkanen, Anna E. Börjesson, Marie K. Lagerquist, Ulf H. Lerner, Fu Ping Zhang, Jan Åke Gustafsson, Matti Poutanen, Claes Ohlsson

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)14972-14977
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number48
StatePublished - Dec 1 2015


  • Cortical bone
  • Estrogen
  • Trabecular bone
  • Transgenic mice
  • WNT16

ASJC Scopus subject areas

  • General


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