Magel2 Modulates Bone Remodeling and Mass in Prader-Willi Syndrome by Affecting Oleoyl Serine Levels and Activity
| Autor: | Alina Nemirovski, Malka Attar-Namdar, Yshaia Langer, Yankel Gabet, Joseph Tam, Raphael Mechoulam, Shira Hirsch, Reem Smoum, Asaad Gammal, Rivka Hadar, Yehuda Pollak, Saja Baraghithy, Megan E. Rech, Itai Bab, Adi Drori, Christian P. Schaaf, Varda Gross-Tsur |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Endocrinology Diabetes and Metabolism Osteoporosis Osteoclasts 030209 endocrinology & metabolism Bone remodeling Serine 03 medical and health sciences Mice 0302 clinical medicine Osteoclast Antigens Neoplasm Bone Density Osteogenesis Internal medicine medicine Animals Humans Orthopedics and Sports Medicine Mice Knockout Osteoblasts business.industry Genetic disorder Proteins Osteoblast medicine.disease 030104 developmental biology medicine.anatomical_structure Endocrinology Bone Remodeling business Prader-Willi Syndrome Homeostasis Hormone |
| Zdroj: | Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 34(1) |
| ISSN: | 1523-4681 |
| Popis: | 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. © 2018 American Society for Bone and Mineral Research. |
| Databáze: | OpenAIRE |
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