Document Type

Journal Article

Date of this Version

8-10-2014

Publication Source

Nature Medicine

Volume

20

Start Page

1009

Last Page

1017

DOI

10.1038/nm.3586

Abstract

Aging-related bone loss and osteoporosis affect millions of people worldwide. Chronic inflammation associated with aging promotes bone resorption and impairs bone formation. Here we show that Wnt4 attenuates bone loss in osteoporosis and skeletal aging mouse models by inhibiting nuclear factor-κB (NF-κB) via noncanonical Wnt signaling. Transgenic mice expressing Wnt4 from osteoblasts were significantly protected from bone loss and chronic inflammation induced by ovariectomy, tumor necrosis factor or natural aging. In addition to promoting bone formation, Wnt4 inhibited osteoclast formation and bone resorption. Mechanistically, Wnt4 inhibited NF-κB activation mediated by transforming growth factor-β–activated kinase-1 (Tak1) in macrophages and osteoclast precursors independently of β-catenin. Moreover, recombinant Wnt4 alleviated bone loss and inflammation by inhibiting NF-κB in vivo in mouse models of bone disease. Given its dual role in promoting bone formation and inhibiting bone resorption, our results suggest that Wnt4 signaling could be an attractive therapeutic target for treating osteoporosis and preventing skeletal aging.

Comments

The author manuscript, found here, is titled "Non-Canonical Wnt4 Prevents Skeletal Aging and Inflammation by Inhibiting NF-κB" but was published in its final form as "Wnt4 Signaling Prevents Skeletal Aging and Inflammation by Inhibiting Nuclear Factor-κB."

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Date Posted: 02 April 2015

This document has been peer reviewed.