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Dimorphic effects of Notch signaling in bone homeostasis

Nature Medicine volume 14, pages 299–305 (2008)Cite this article

Abstract

Notch signaling is a key mechanism in the control of embryogenesis. However, its in vivo function during mesenchymal cell differentiation, and, specifically, in bone homeostasis, remains largely unknown. Here, we show that osteoblast-specific gain of Notch function causes severe osteosclerosis owing to increased proliferation of immature osteoblasts. Under these pathological conditions, Notch stimulates early osteoblastic proliferation by upregulating the genes encoding cyclin D, cyclin E and Sp7 (osterix). The intracellular domain of Notch1 also regulates terminal osteoblastic differentiation by directly binding Runx2 and repressing its transactivation function. In contrast, loss of all Notch signaling in osteoblasts, generated by deletion of the genes encoding presenilin-1 and presenilin-2 in bone, is associated with late-onset, age-related osteoporosis, which in turn results from increased osteoblast-dependent osteoclastic activity due to decreased osteoprotegerin mRNA expression in these cells. Together, these findings highlight the potential dimorphic effects of Notch signaling in bone homeostasis and may provide direction for novel therapeutic applications.

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Figure 1: Gain of Notch function in transgenic mice cause osteosclerosis.
Figure 2: Notch regulates key osteoblast transcription factors and cell cycle proteins.
Figure 3: Loss of Notch signaling via presenilin deletion causes osteoporosis.
Figure 4: Loss of Notch signaling through presenilin deletion increases the osteoclastogenic pool.
Figure 5: Model for Notch's dimorphic effects in bone homeostasis.

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Acknowledgements

We thank T. Kadesch (University of Pennsylvania) for Myc-His–tagged N1ICD, GST-NICDΔTAD and GST-NICDΔRA, G. Karsenty (Columbia University) for Col1a1-Cre mice, M.S. Nanes (Emory University) for osterix-luciferase and −1269/91 Osx-p-luc, and L. Donehower (Baylor College of Medicine) for antibody to p53. We thank M. Acar and O. Sirin for technical assistance. This work was supported by US National Institutes of Health grants ES11253 (B.L.), HD22657 (B.L.), DE016990 (B.L.) and AR43510 (B.F.B.).

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Author notes

  1. Zhenqiang Yao and Tao Yang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, 7703, Texas, USA

    Feyza Engin, Tao Yang, Guang Zhou, Terry Bertin, Ming Ming Jiang, Yuqing Chen, Hui Zheng & Brendan Lee

  2. Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, 14642, New York, USA

    Zhenqiang Yao & Brendan F Boyce

  3. Howard Hughes Medical Institute, One Baylor Plaza, Houston, 77030, Texas, USA

    Ming Ming Jiang, Yuqing Chen & Brendan Lee

  4. Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, 77030, Texas, USA

    Lisa Wang

  5. Department of Molecular Virology and Microbiology, Baylor College of Medicine, One Baylor Plaza, Houston, 77030, Texas, USA

    Richard E Sutton

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  1. Feyza Engin
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Correspondence to Brendan Lee.

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Engin, F., Yao, Z., Yang, T. et al. Dimorphic effects of Notch signaling in bone homeostasis. Nat Med 14, 299–305 (2008). https://doi.org/10.1038/nm1712

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