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.
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Change history
04 August 2015
In the published article, we, the authors, interpreted the data in Figure 4a–e to mean that transgenic expression of Wnt4 in osteoblasts of mice protects them from age-related bone loss. However, after publication it has been pointed out to us that, at all the ages examined, the transgenic mice had greater trabecular bone mass than control mice. Thus, we have re-examined the data in Figure 4b using statistical tests to examine the relative rate of change of bone mass and bone volume/total volume over the four age groups presented, and we find there is no statistical difference for the rate of these parameters between the transgenic and control groups. Thus, our conclusions with respect to this aspect of the study were incorrect, and further we conclude that we placed an improper emphasis on these findings in the title of the paper. We have also reanalyzed the data in the rest of the paper using more proper statistical tests in several instances. In particular, the standard deviations in Figures 1g, 1h, 2c–e, 3c–e, 4d, 4f, 6d, 6e and Supplementary Figure 6g were reported inappropriately. We used values from each histology image (3–6 images per mouse) as individual data points, instead of the mean values for each mouse, leading to an increased standard deviation. Furthermore, for morphometric and serum analysis in Figures 2, 3, 4g,h, 6 and Supplementary Figure 6, one-way analysis of variance with Tukey's post hoc test should have been used to account for multiple comparisons and adjustments for type I errors. Upon reanalysis, the comparison of osteoclast numbers/bone surface between the wild-type (WT) sham group and the Ob-Wnt4 sham group in Figure 2e, and the comparison of osteoclast surface/bone surface between the WT and Wnt4 groups in Figure 3e lost statistical significance, as was stated in the article. Although our conclusion about the effect of transgenic expression of Wnt4 in osteoblasts on skeletal aging appears to be incorrect, the above changes regarding our statistical analyses do not alter the conclusions drawn in the manuscript with respect to the effect of Wnt4 transgenic expression on bone mass compared to non-transgenic mice at static time points, the effect of recombinant Wnt4 on bone loss in the ovariectomy model nor on the molecular mechanisms for these effects. Nonetheless, we apologize for any confusion these original analyses or conclusions may have caused.
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Acknowledgements
We thank J. Adams for valuable advice. This work was supported by the US National Institute of Dental and Craniofacial Research grants DE19412 and DE16513 (to C.-Y.W.), the US National Institute of Arthritis and Musculoskeletal and Skin Diseases grant AR63089 (to C.-Y.W.) and the UCLA Broad Stem Cell Research Center Research Award (to C.-Y.W.).
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B.Y., J.C., Y.L., J.L. and K.K. performed the experiments. K.A.-H., D.T.G., N.-H.P. and C.-Y.W. designed experiments and analyzed data. B.Y. and C.-Y.W. wrote the manuscript.
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Yu, B., Chang, J., Liu, Y. et al. Wnt4 signaling prevents skeletal aging and inflammation by inhibiting nuclear factor-κB. Nat Med 20, 1009–1017 (2014). https://doi.org/10.1038/nm.3586
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DOI: https://doi.org/10.1038/nm.3586
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