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J Bone Miner Res. 2019 Jan;34(1):93-105. doi: 10.1002/jbmr.3591. Epub 2018 Oct 22.

Magel2 Modulates Bone Remodeling and Mass in Prader-Willi Syndrome by Affecting Oleoyl Serine Levels and Activity.

Author information

1
Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
2
Medicinal Chemistry Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
3
Bone Laboratory, Institute for Dental Research, Faculty of Dentistry, The Hebrew University of Jerusalem, Jerusalem, Israel.
4
Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
5
Neuropediatric Unit, Department of Pediatrics, Shaare Zedek Medical Center, Jerusalem, Israel.
6
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
7
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.

Abstract

Among a multitude of hormonal and metabolic complications, individuals with Prader-Willi syndrome (PWS) exhibit significant bone abnormalities, including decreased BMD, osteoporosis, and subsequent increased fracture risk. Here we show in mice that loss of Magel2, a maternally imprinted gene in the PWS critical region, results in reduced bone mass, density, and strength, corresponding to that observed in humans with PWS, as well as in individuals suffering from Schaaf-Yang syndrome (SYS), a genetic disorder caused by a disruption of the MAGEL2 gene. The low bone mass phenotype in Magel2-/- mice was attributed to reduced bone formation rate, increased osteoclastogenesis and osteoclast activity, and enhanced trans-differentiation of osteoblasts to adipocytes. The absence of Magel2 in humans and mice resulted in reduction in the fatty acid amide bone homeostasis regulator, N-oleoyl serine (OS), whose levels were positively linked with BMD in humans and mice as well as osteoblast activity. Attenuating the skeletal abnormalities in Magel2-/- mice was achieved with chronic administration of a novel synthetic derivative of OS. Taken together, Magel2 plays a key role in modulating bone remodeling and mass in PWS by affecting OS levels and activity. The use of potent synthetic analogs of OS should be further tested clinically as bone therapeutics for treating bone loss.

KEYWORDS:

BONE REMODELING; MAGEL2; OLEOYL SERINE; PRADER-WILLI SYNDROME; SCHAAF-YANG SYNDROME

PMID:
30347474
DOI:
10.1002/jbmr.3591

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