Article abstract
Nature Medicine 14, 299 - 305 (2008)
Published online: 24 February 2008 | doi:10.1038/nm1712
Dimorphic effects of Notch signaling in bone homeostasis
Feyza Engin1, Zhenqiang Yao2,6, Tao Yang1,6, Guang Zhou1, Terry Bertin1, Ming Ming Jiang1,3, Yuqing Chen1,3, Lisa Wang4, Hui Zheng1, Richard E Sutton5, Brendan F Boyce2 & Brendan Lee1,3
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.
- Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 7703, USA
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York 14642, USA
- Howard Hughes Medical Institute, One Baylor Plaza, Houston, Texas 77030, USA
- Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
- These authors contributed equally to this work.
Correspondence to: Brendan Lee1,3 e-mail: blee@bcm.tmc.edu