title: Anabolic actions of Notch on mature bone.
abstract: Notch controls skeletogenesis, but its role in the remodeling of adult bone remains conflicting. In mature mice, the skeleton can become osteopenic or osteosclerotic depending on the time point at which Notch is activated or inactivated. Using adult EGFP reporter mice, we find that Notch expression is localized to osteocytes embedded within bone matrix. Conditional activation of Notch signaling in osteocytes triggers profound bone formation, mainly due to increased mineralization, which rescues both age-associated and ovariectomy-induced bone loss and promotes bone healing following osteotomy. In parallel, mice rendered haploinsufficient in γ-secretase presenilin-1 (Psen1), which inhibits downstream Notch activation, display almost-absent terminal osteoblast differentiation. Consistent with this finding, pharmacologic or genetic disruption of Notch or its ligand Jagged1 inhibits mineralization. We suggest that stimulation of Notch signaling in osteocytes initiates a profound, therapeutically relevant, anabolic response.
authors.affiliation: The Mount Sinai Bone Program, Department of Medicine, Mount Sinai School of Medicine, NY 10029; State Key Laboratory of Oral Disease, West China School of Stomatology, Sichuan University, Sichuan 610041, China; mone.zaidi@mssm.edu liupossible@gmail.com maria.new@mssm.edu.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Oral Disease, West China School of Stomatology, Sichuan University, Sichuan 610041, China;
authors.forename: Yilin
authors.initials: Y
authors.lastname: Ping
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, NY 10029;
authors.forename: Meng
authors.initials: M
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Oral Disease, West China School of Stomatology, Sichuan University, Sichuan 610041, China;
authors.forename: Demao
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, NY 10029;
authors.forename: Connie
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, CT 06520;
authors.forename: Samir
authors.initials: S
authors.lastname: Zaidi
authors.affiliation: School of Stomatology, Wuhan University, Wuhan 430079, China;
authors.forename: Song
authors.initials: S
authors.lastname: Gao
authors.affiliation: The Mount Sinai Bone Program, Department of Medicine, Mount Sinai School of Medicine, NY 10029; School of Stomatology, Wuhan University, Wuhan 430079, China;
authors.forename: Yaoting
authors.initials: Y
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Oral Disease, West China School of Stomatology, Sichuan University, Sichuan 610041, China;
authors.forename: Feng
authors.initials: F
authors.lastname: Lou
authors.affiliation: State Key Laboratory of Oral Disease, West China School of Stomatology, Sichuan University, Sichuan 610041, China;
authors.forename: Fanyuan
authors.initials: F
authors.lastname: Yu
authors.affiliation: The Mount Sinai Bone Program, Department of Medicine, Mount Sinai School of Medicine, NY 10029;
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
authors.affiliation: The Mount Sinai Bone Program, Department of Medicine, Mount Sinai School of Medicine, NY 10029;
authors.forename: Agnes
authors.initials: A
authors.lastname: Stachnik
authors.affiliation: State Key Laboratory of Oral Disease, West China School of Stomatology, Sichuan University, Sichuan 610041, China;
authors.forename: Mingru
authors.initials: M
authors.lastname: Bai
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, NY 10029;
authors.forename: Chengguo
authors.initials: C
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Oral Disease, West China School of Stomatology, Sichuan University, Sichuan 610041, China;
authors.forename: Liaoran
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oral Disease, West China School of Stomatology, Sichuan University, Sichuan 610041, China;
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, NY 10029;
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Mount Sinai School of Medicine, NY 10029; mone.zaidi@mssm.edu liupossible@gmail.com maria.new@mssm.edu.
authors.forename: Maria I
authors.initials: MI
authors.lastname: New
authors.affiliation: Department of Reconstructive Sciences, School of Dental Medicine, University of Connecticut School of Medicine, Farmington, CT 06030.
authors.forename: David W
authors.initials: DW
authors.lastname: Rowe
authors.affiliation: The Mount Sinai Bone Program, Department of Medicine, Mount Sinai School of Medicine, NY 10029;
authors.forename: Tony
authors.initials: T
authors.lastname: Yuen
authors.affiliation: The Mount Sinai Bone Program, Department of Medicine, Mount Sinai School of Medicine, NY 10029;
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.affiliation: The Mount Sinai Bone Program, Department of Medicine, Mount Sinai School of Medicine, NY 10029; Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, NY 10029; mone.zaidi@mssm.edu liupossible@gmail.com maria.new@mssm.edu.
authors.forename: Mone
authors.initials: M
authors.lastname: Zaidi
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism*; D002113:Calcification, Physiologic / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D000072100:Jagged-1 Protein / Q000235:genetics; D008297:Male; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000502:physiology; D053764:Presenilin-1 / Q000235:genetics; D051880:Receptors, Notch / Q000378:metabolism*; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D053764:Presenilin-1; D051880:Receptors, Notch; C485184:enhanced green fluorescent protein; C580804:presenilin 1, mouse; D049452:Green Fluorescent Proteins
keywords: aging; osteoporosis; skeletal mineralization; therapeutic target