Abstract
Postnatal bone marrow houses mesenchymal progenitor cells that are osteoblast precursors. These cells have established therapeutic potential, but they are difficult to maintain and expand in vitro, presumably because little is known about the mechanisms controlling their fate decisions. To investigate the potential role of Notch signaling in osteoblastogenesis, we used conditional alleles to genetically remove components of the Notch signaling system during skeletal development. We found that disruption of Notch signaling in the limb skeletogenic mesenchyme markedly increased trabecular bone mass in adolescent mice. Notably, mesenchymal progenitors were undetectable in the bone marrow of mice with high bone mass. As a result, these mice developed severe osteopenia as they aged. Moreover, Notch signaling seemed to inhibit osteoblast differentiation through Hes or Hey proteins, which diminished Runx2 transcriptional activity via physical interaction. These results support a model wherein Notch signaling in bone marrow normally acts to maintain a pool of mesenchymal progenitors by suppressing osteoblast differentiation. Thus, mesenchymal progenitors may be expanded in vitro by activating the Notch pathway, whereas bone formation in vivo may be enhanced by transiently suppressing this pathway.
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Acknowledgements
This work was supported in part by US National Institutes of Health grants DK065789 (F.L.), HD044056 (R.K.), AR046852 (F.P.R.), AR046523 (S.L.T.), DK11794 (H.M.K.) and 5T32AR07033 (M.J.H.). We thank R. Civitelli (Washington University) for pCMV-Runx2 and p60SE2-Luc, R. Kageyama (Kyoto University) for pSV2-CMV-Hes1, P. Robey and S. Kuznetsov for advice on bone marrow CFU-F assays and J. Shen (Harvard Medical School) and Thomas Gridley (Jackson Laboratory) for mouse strains. We also thank D. Towler and M. Silva for their help with the response to reviewers' comments.
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M.J.H., animal studies and figure preparation; X.T., cell culture work and animal studies; X.W. coimmunoprecipitation experiments; S.B., H.Z., F.P.R. and S.L.T., TRAP staining, serum CTX1 assays and discussion; T.K. and H.M.K., Col1-Cre mice; R.K., Notch reagents and manuscript editing; F.L., project directing, figure preparation and manuscript writing.
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Hilton, M., Tu, X., Wu, X. et al. Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat Med 14, 306–314 (2008). https://doi.org/10.1038/nm1716
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DOI: https://doi.org/10.1038/nm1716
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