Journal
NATURE MEDICINE
Volume 20, Issue 9, Pages 1009-1017Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3586
Keywords
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Funding
- US National Institute of Dental and Craniofacial [DE19412, DE16513]
- US National Institute of Arthritis and Musculoskeletal and Skin Diseases [AR63089]
- UCLA Broad Stem Cell Research Center Research Award
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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-kappa B (NF-kappa B) 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-kappa B activation mediated by transforming growth factor-beta-activated kinase-1 (Tak1) in macrophages and osteoclast precursors independently of beta-catenin. Moreover, recombinant Wnt4 alleviated bone loss and inflammation by inhibiting NF-kappa B 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.
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