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

Saja Baraghithy, Reem Smoum, Adi Drori, Rivka Hadar, Asaad Gammal, Shira Hirsch, Malka Attar-Namdar, Alina Nemirovski, Yankel Gabet, Yshaia Langer, Yehuda Pollak, Christian Patrick Schaaf, Megan Elizabeth Rech, Varda Gross-Tsur, Itai Bab, Raphael Mechoulam, Joseph Tam*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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.

Original languageAmerican English
Pages (from-to)93-105
Number of pages13
JournalJournal of Bone and Mineral Research
Volume34
Issue number1
DOIs
StatePublished - Jan 2019

Bibliographical note

Funding Information:
This work was supported by the Foundation for Prader Willi Research (FPWR), the Israel Science Foundation (ISF grant #617/14), and NIH grant U54HD08302 (IDDRC, Clinical Translational Core). This work was supported, in part, by a generous scholarship provided by the Israeli Ministry of Science & Technology to SB. We are grateful to Dr.

Funding Information:
This work was supported by the Foundation for Prader Willi Research (FPWR), the Israel Science Foundation (ISF grant #617/ 14), and NIH grant U54HD08302 (IDDRC, Clinical Translational Core). This work was supported, in part, by a generous scholarship provided by the Israeli Ministry of Science & Technology to SB. We are grateful to Dr. Dinorah Barasch and Ms. Sivane Brodach for their technical assistance with the LC-MS/ MS and imaging analyses, respectively, as well as to Nava Badichi for administrative assistance in coordinating blood sampling and data analysis.

Publisher Copyright:
© 2018 American Society for Bone and Mineral Research

Keywords

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

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