Abstract
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.
Highlights
Bone is a remarkably intricate and metabolically active organ that serves essential functions, including providing the structural and mechanical integrity required for locomotion and protection of vital organs, maintenance of mineral homeostasis, and hematopoiesis [1,2]
A few endogenous individual members of the fatty acyl amide (FAA) family have been known since the mid-20th century, it is the discovery of arachidonoyl ethanolamide (AEA) or anandamide [22] that boosted the modern, large-scale investigation of FAAs and their designation as a family
A growing body of evidence has indicated that FAAs are present in bone cells and that they play an important role in the regulation of bone mass [11,23]
Summary
Bone is a remarkably intricate and metabolically active organ that serves essential functions, including providing the structural and mechanical integrity required for locomotion and protection of vital organs, maintenance of mineral homeostasis, and hematopoiesis [1,2]. It is well established that the roles of lipids are not solely limited to energy storage or as structural components of the cell membrane [11]—they include their activity as signaling molecules, which are important in several physiological and pathological conditions [12,13,14,15]. A growing body of evidence has indicated that FAAs are present in bone cells and that they play an important role in the regulation of bone mass [11,23]. Such an example is N-oleoyl-l-serine (OS); investigation into its metabolic activity in bone demonstrated that it is a potent anti-osteoporotic agent in both in vitro and in vivo models [24]. Loss of Magel, one of the genes in the PWS-critical region, induced a significant reduction in bone mass that was correlated with reduced circulating levels of OS both in humans and mice
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