title: Osteoblast lineage-specific effects of notch activation in the skeleton.
abstract: Transgenic overexpression of the Notch1 intracellular domain inhibits osteoblast differentiation and causes osteopenia, and inactivation of Notch1 and Notch2 increases bone volume transiently and induces osteoblastic differentiation. However, the biology of Notch is cell-context-dependent, and consequences of Notch activation in cells of the osteoblastic lineage at various stages of differentiation and in osteocytes have not been defined. For this purpose, Rosa(Notch) mice, where a loxP-flanked STOP cassette placed between the Rosa26 promoter and the NICD coding sequence, were crossed with transgenics expressing the Cre recombinase under the control of the Osterix (Osx), Osteocalcin (Oc), Collagen 1a1 (Col2.3), or Dentin matrix protein1 (Dmp1) promoters. At 1 month, Osx-Cre;Rosa(Notch) and Oc-Cre;Rosa(Notch) mice exhibited osteopenia due to impaired bone formation. In contrast, Col2.3-Cre;Rosa(Notch) and Dmp1-Cre;Rosa(Notch) exhibited increased femoral trabecular bone volume due to a decrease in osteoclast number and eroded surface. In the four lines studied, cortical bone was either not present, was porous, or had the appearance of trabecular bone. Oc-Cre;Rosa(Notch) and Col2.3-Cre;Rosa(Notch) mice exhibited early lethality so that their adult phenotype was not established. At 3 months, Osx-Cre;Rosa(Notch) and Dmp1-Cre;Rosa(Notch) mice displayed increased bone volume, and increased osteoblasts although calcein-demeclocycline labels were diffuse and fragmented, indicating abnormal bone formation. In conclusion, Notch effects in the skeleton are cell-context-dependent. When expressed in immature osteoblasts, Notch arrests their differentiation, causing osteopenia, and when expressed in osteocytes, it causes an initial suppression of bone resorption and increased bone volume, a phenotype that evolves as the mice mature.
authors.affiliation: Department of Research, Saint Francis Hospital and Medical Center, 114 Woodland Street, Hartford, CT 06105-1299, USA. ecanalis@stfranciscare.org
authors.forename: Ernesto
authors.initials: E
authors.lastname: Canalis
authors.forename: Kristen
authors.initials: K
authors.lastname: Parker
authors.forename: Jian Q
authors.initials: JQ
authors.lastname: Feng
authors.forename: Stefano
authors.initials: S
authors.lastname: Zanotti
mesh_terms: D000818:Animals; D001846:Bone Development / Q000502:physiology; D001851:Bone Diseases, Metabolic / Q000235:genetics* / Q000473:pathology; D001842:Bone and Bones / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics*; D024043:Collagen Type II / Q000502:physiology; D005260:Female; D005269:Femur / Q000166:cytology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology*; D015675:Osteocalcin / Q000502:physiology; D010012:Osteogenesis / Q000235:genetics*; D010641:Phenotype; D051880:Receptors, Notch / Q000235:genetics*; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000502:physiology
chemical_list: D024043:Collagen Type II; D051880:Receptors, Notch; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D015675:Osteocalcin