title: Dimorphic effects of Notch signaling in bone homeostasis.
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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 7703, USA.
authors.forename: Feyza
authors.initials: F
authors.lastname: Engin
authors.forename: Zhenqiang
authors.initials: Z
authors.lastname: Yao
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.forename: Guang
authors.initials: G
authors.lastname: Zhou
authors.forename: Terry
authors.initials: T
authors.lastname: Bertin
authors.forename: Ming Ming
authors.initials: MM
authors.lastname: Jiang
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Chen
authors.forename: Lisa
authors.initials: L
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.forename: Richard E
authors.initials: RE
authors.lastname: Sutton
authors.forename: Brendan F
authors.initials: BF
authors.lastname: Boyce
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D015675:Osteocalcin / Q000378:metabolism; D010024:Osteoporosis / Q000378:metabolism; D010026:Osteosclerosis / Q000235:genetics / Q000378:metabolism; D053763:Presenilins / Q000172:deficiency; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors; D014162:Transfection
chemical_list: D053763:Presenilins; D051880:Receptors, Notch; D014157:Transcription Factors; D015675:Osteocalcin