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Nat Med. 2014 Sep;20(9):1009-17. doi: 10.1038/nm.3586. Epub 2014 Aug 10.

Wnt4 signaling prevents skeletal aging and inflammation by inhibiting nuclear factor-κB.

Author information

1
1] Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles (UCLA), Los Angeles, California, USA. [2].
2
Department of Prosthodontics, School and Hospital of Stomatology, Peking University, Beijing, China.
3
Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles (UCLA), Los Angeles, California, USA.
4
Eng. A.B. Research Center for Growth Factors and Bone Regeneration, Division of Periodontology, College of Dentistry, King Saud University, Riyadh, Saudi Arabia.
5
Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
6
1] Division of Diagnostic and Surgical Sciences, School of Dentistry, UCLA, Los Angeles, California, USA. [2] Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
7
1] Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles (UCLA), Los Angeles, California, USA. [2] Broad Stem Cell Research Center, UCLA, Los Angeles, California, USA. [3] Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, UCLA, Los Angeles, California, USA.

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.

PMID:
25108526
PMCID:
PMC4159424
DOI:
10.1038/nm.3586
[Indexed for MEDLINE]
Free PMC Article

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