title: Notch signaling in osteocytes differentially regulates cancellous and cortical bone remodeling.
abstract: Notch receptors play a role in skeletal development and homeostasis, and Notch activation in undifferentiated and mature osteoblasts causes osteopenia. In contrast, Notch activation in osteocytes increases bone mass, but the mechanisms involved and exact functions of Notch are not known. In this study, Notch1 and -2 were inactivated preferentially in osteocytes by mating Notch1/2 conditional mice, where Notch alleles are flanked by loxP sequences, with transgenics expressing Cre directed by the Dmp1 (dentin matrix protein 1) promoter. Notch1/2 conditional null male and female mice exhibited an increase in trabecular bone volume due to an increase in osteoblasts and decrease in osteoclasts. In male null mice, this was followed by an increase in osteoclast number and normalization of bone volume. To activate Notch preferentially in osteocytes, Dmp1-Cre transgenics were crossed with Rosa(Notch) mice, where a loxP-flanked STOP cassette is placed between the Rosa26 promoter and Notch1 intracellular domain sequences. Dmp1-Cre(+/-);Rosa(Notch) mice exhibited an increase in trabecular bone volume due to decreased bone resorption and an increase in cortical bone due to increased bone formation. Biomechanical and chemical properties were not affected. Osteoprotegerin mRNA was increased, sclerostin and dickkopf1 mRNA were decreased, and Wnt signaling was enhanced in Dmp1-Cre(+/-);Rosa(Notch) femurs. Botulinum toxin A-induced muscle paralysis caused pronounced osteopenia in control mice, but bone mass was preserved in mice harboring the Notch activation in osteocytes. In conclusion, Notch plays a unique role in osteocytes, up-regulates osteoprotegerin and Wnt signaling, and differentially regulates trabecular and cortical bone homeostasis.
authors.affiliation: From the Department of Research, Saint Francis Hospital and Medical Center, Hartford, Connecticut 06105,; the University of Connecticut School of Medicine, Farmington, Connecticut 06030,. Electronic address: ecanalis@stfranciscare.org.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Canalis
authors.affiliation: the Department of Orthopedic Surgery, University of Connecticut Health Center, Farmington, Connecticut 06030, and.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Adams
authors.affiliation: the Hospital for Special Surgery, New York, New York 10021.
authors.forename: Adele
authors.initials: A
authors.lastname: Boskey
authors.affiliation: From the Department of Research, Saint Francis Hospital and Medical Center, Hartford, Connecticut 06105.
authors.forename: Kristen
authors.initials: K
authors.lastname: Parker
authors.affiliation: From the Department of Research, Saint Francis Hospital and Medical Center, Hartford, Connecticut 06105.
authors.forename: Lauren
authors.initials: L
authors.lastname: Kranz
authors.affiliation: From the Department of Research, Saint Francis Hospital and Medical Center, Hartford, Connecticut 06105,; the University of Connecticut School of Medicine, Farmington, Connecticut 06030.
authors.forename: Stefano
authors.initials: S
authors.lastname: Zanotti
mesh_terms: D000818:Animals; D001851:Bone Diseases, Metabolic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016723:Bone Remodeling; D019274:Botulinum Toxins, Type A / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009465:Neuromuscular Agents / Q000009:adverse effects / Q000494:pharmacology; D010011:Osteocytes / Q000378:metabolism* / Q000473:pathology; D053244:Osteoprotegerin / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D009465:Neuromuscular Agents; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; D053244:Osteoprotegerin; D012333:RNA, Messenger; D051881:Receptor, Notch1; D051883:Receptor, Notch2; C506031:Tnfrsf11b protein, mouse; D019274:Botulinum Toxins, Type A
keywords: Bone; Bone Remodeling; Cell Signaling; Disuse Osteoporosis; Gene Knockout; Notch; Osteocyte; Receptors; Skeletal Architecture; Wnt Pathway