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Proc Natl Acad Sci U S A. 2016 Apr 12;113(15):E2152-61. doi: 10.1073/pnas.1603399113. Epub 2016 Mar 28.

Anabolic actions of Notch on mature bone.

Author information

1
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.
2
State Key Laboratory of Oral Disease, West China School of Stomatology, Sichuan University, Sichuan 610041, China;
3
Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, NY 10029;
4
Department of Genetics, Yale School of Medicine, New Haven, CT 06520;
5
School of Stomatology, Wuhan University, Wuhan 430079, China;
6
The Mount Sinai Bone Program, Department of Medicine, Mount Sinai School of Medicine, NY 10029; School of Stomatology, Wuhan University, Wuhan 430079, China;
7
The Mount Sinai Bone Program, Department of Medicine, Mount Sinai School of Medicine, NY 10029;
8
Department of Pediatrics, Mount Sinai School of Medicine, NY 10029; mone.zaidi@mssm.edu liupossible@gmail.com maria.new@mssm.edu.
9
Department of Reconstructive Sciences, School of Dental Medicine, University of Connecticut School of Medicine, Farmington, CT 06030.
10
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.

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.

KEYWORDS:

aging; osteoporosis; skeletal mineralization; therapeutic target

PMID:
27036007
PMCID:
PMC4839423
DOI:
10.1073/pnas.1603399113
[Indexed for MEDLINE]
Free PMC Article
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