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Open AccessArticle

HU-671, a Novel Oleoyl Serine Derivative, Exhibits Enhanced Efficacy in Reversing Ovariectomy-Induced Osteoporosis and Bone Marrow Adiposity

1
Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
2
Bone Laboratory, Institute for Dental Research, Faculty of Dentistry, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
3
Medicinal Chemistry Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Prof. Itai Bab passed away.
Academic Editors: Melanie Kelly and Christian Lehmann
Molecules 2019, 24(20), 3719; https://doi.org/10.3390/molecules24203719
Received: 30 August 2019 / Revised: 5 October 2019 / Accepted: 15 October 2019 / Published: 16 October 2019
(This article belongs to the Special Issue Cannabinoids)
Oleoyl serine (OS), an endogenous fatty acyl amide (FAA) found in bone, has been shown to have an anti-osteoporotic effect. OS, being an amide, can be hydrolyzed in the body by amidases. Hindering its amide bond by introducing adjacent substituents has been demonstrated as a successful method for prolonging its skeletal activity. Here, we tested the therapeutic efficacy of two methylated OS derivatives, oleoyl α-methyl serine (HU-671) and 2-methyl-oleoyl serine (HU-681), in an ovariectomized mouse model for osteoporosis by utilizing combined micro-computed tomography, histomorphometry, and cell culture analyses. Our findings indicate that daily treatment for 6 weeks with OS or HU-671 completely rescues bone loss, whereas HU-681 has only a partial effect. The increased bone density was primarily due to enhanced trabecular thickness and number. Moreover, the most effective dose of HU-671 was 0.5 mg/kg/day, an order of magnitude lower than with OS. The reversal of bone loss resulted from increased bone formation and decreased bone resorption, as well as reversal of bone marrow adiposity. These results were further confirmed by determining the serum levels of osteocalcin and type 1 collagen C-terminal crosslinks, as well as demonstrating the enhanced antiadipogenic effect of HU-671. Taken together, these data suggest that methylation interferes with OS’s metabolism, thus enhancing its effects by extending its availability to its target cells. View Full-Text
Keywords: bone lipids; N-acyl amide; oleoyl serine; osteoporosis; bone marrow adiposity bone lipids; N-acyl amide; oleoyl serine; osteoporosis; bone marrow adiposity
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Baraghithy, S.; Smoum, R.; Attar-Namdar, M.; Mechoulam, R.; Bab, I.; Tam, J. HU-671, a Novel Oleoyl Serine Derivative, Exhibits Enhanced Efficacy in Reversing Ovariectomy-Induced Osteoporosis and Bone Marrow Adiposity. Molecules 2019, 24, 3719.

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