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Inhibition of osteoblastic bone formation by nuclear factor-κB

Nature Medicine volume 15, pages 682–689 (2009)Cite this article

Abstract

An imbalance in bone formation relative to bone resorption results in the net bone loss that occurs in osteoporosis and inflammatory bone diseases. Although it is well known how bone resorption is stimulated, the molecular mechanisms that mediate impaired bone formation are poorly understood. Here we show that the time- and stage-specific inhibition of endogenous inhibitor of κB kinase (IKK)–nuclear factor-κB (NF-κB) in differentiated osteoblasts substantially increases trabecular bone mass and bone mineral density without affecting osteoclast activities in young mice. Moreover, inhibition of IKK–NF-κB in differentiated osteoblasts maintains bone formation, thereby preventing osteoporotic bone loss induced by ovariectomy in adult mice. Inhibition of IKK–NF-κB enhances the expression of Fos-related antigen-1 (Fra-1), an essential transcription factor involved in bone matrix formation in vitro and in vivo. Taken together, our results suggest that targeting IKK–NF-κB may help to promote bone formation in the treatment of osteoporosis and other bone diseases.

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Figure 1: Generation of transgenic mice specifically expressing IKK-DN in differentiated osteoblasts.
Figure 2: Inhibition of NF-κB by IKK-DN in mature osteoblasts enhances bone formation in young mice.
Figure 3: Inhibition of NF-κB in mature osteoblasts enhances bone formation in a cell-autonomous fashion.
Figure 4: Inhibition of NF-κB in mature osteoblasts prevents trabecular bone loss induced by ovariectomy in adult mice.
Figure 5: Inhibition of NF-κB in mature osteoblasts prevents bone loss by maintaining osteoblast functions in adult mice.
Figure 6: Inhibition of NF-κB promotes osteoblast activities by inducing Fra-1 expression.

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Acknowledgements

We thank J. Adams for valuable advice and G. Karsenty (Columbia University) for Col1a1 promoter and T. Gilmore (Boston University) for c-Rel vector. This work was supported by US National Institute of Dental and Craniofacial Research grants (DE17684, DE019412, DE1016513, DE13848 and DE018890) and US National Institute of Diabetes and Kidney Disease grants (DK053904).

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Authors and Affiliations

  1. Division of Oral Biology and Medicine, Laboratory of Molecular Signaling, School of Dentistry and Jonsson Comprehensive Cancer Center, University of California–Los Angeles, Los Angeles, California, USA

    Jia Chang, Eric Tang, Zhipeng Fan & Cun-Yu Wang

  2. Department of Biologic and Materials Sciences, Ann Arbor, Michigan, USA

    Zhuo Wang & Paul H Krebsbach

  3. Department of Periodontics and Oral Medicine, School of Dentistry, Ann Arbor, Michigan, USA

    Laurie McCauley & Renny Franceschi

  4. Department of Pathology, School of Medicine, University of Michigan, Ann Arbor, Michigan, USA

    Laurie McCauley

  5. Department of Pharmacology and Comprehensive Cancer Center, University of California–San Diego, San Diego, California, USA

    Kunliang Guan

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Contributions

J.C. performed the majority of the experiments, analyzed data and prepared figures. Z.W. performed μCT and analyzed data. E.T. and Z.F. performed complementary DNA subcloning. L.M. helped with experiment designs and the preparation of manuscript. R.F. provided reagents and helped with the preparation of manuscript. K.G. provided reagents and helped with the preparation of manuscript. P.H.K. helped with μCT and the preparation of manuscript. C.-Y.W. designed experiments, analyzed data and wrote the manuscript.

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Correspondence to Cun-Yu Wang.

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Supplementary Figs. 1–7 and Supplementary Methods (PDF 1082 kb)

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Chang, J., Wang, Z., Tang, E. et al. Inhibition of osteoblastic bone formation by nuclear factor-κB. Nat Med 15, 682–689 (2009). https://doi.org/10.1038/nm.1954

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