title: Oleoyl serine, an endogenous N-acyl amide, modulates bone remodeling and mass.
abstract: Bone mass is determined by a continuous remodeling process, whereby the mineralized matrix is being removed by osteoclasts and subsequently replaced with newly formed bone tissue produced by osteoblasts. Here we report the presence of endogenous amides of long-chain fatty acids with amino acids or with ethanolamine (N-acyl amides) in mouse bone. Of these compounds, N-oleoyl-l-serine (OS) had the highest activity in an osteoblast proliferation assay. In these cells, OS triggers a Gi-protein-coupled receptor and Erk1/2. It also mitigates osteoclast number by promoting osteoclast apoptosis through the inhibition of Erk1/2 phosphorylation and receptor activator of nuclear-κB ligand (RANKL) expression in bone marrow stromal cells and osteoblasts. In intact mice, OS moderately increases bone volume density mainly by inhibiting bone resorption. However, in a mouse ovariectomy (OVX) model for osteoporosis, OS effectively rescues bone loss by increasing bone formation and markedly restraining bone resorption. The differential effect of exogenous OS in the OVX vs. intact animals is apparently a result of an OVX-induced decrease in skeletal OS levels. These data show that OS is a previously unexplored lipid regulator of bone remodeling. It represents a lead to antiosteoporotic drug discovery, advantageous to currently available therapies, which are essentially either proformative or antiresorptive.
authors.affiliation: Bone Laboratory and Institute of Drug Research, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
authors.forename: Reem
authors.initials: R
authors.lastname: Smoum
authors.forename: Arik
authors.initials: A
authors.lastname: Bar
authors.forename: Bo
authors.initials: B
authors.lastname: Tan
authors.forename: Garry
authors.initials: G
authors.lastname: Milman
authors.forename: Malka
authors.initials: M
authors.lastname: Attar-Namdar
authors.forename: Orr
authors.initials: O
authors.lastname: Ofek
authors.forename: Jordyn M
authors.initials: JM
authors.lastname: Stuart
authors.forename: Alon
authors.initials: A
authors.lastname: Bajayo
authors.forename: Joseph
authors.initials: J
authors.lastname: Tam
authors.forename: Vardit
authors.initials: V
authors.lastname: Kram
authors.forename: David
authors.initials: D
authors.lastname: O'Dell
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Walker
authors.forename: Heather B
authors.initials: HB
authors.lastname: Bradshaw
authors.forename: Itai
authors.initials: I
authors.lastname: Bab
authors.forename: Raphael
authors.initials: R
authors.lastname: Mechoulam
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D015519:Bone Density / Q000187:drug effects*; D016723:Bone Remodeling / Q000187:drug effects*; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009829:Oleic Acids / Q000378:metabolism / Q000494:pharmacology*; D010006:Osteoblasts / Q000378:metabolism*; D010024:Osteoporosis / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012694:Serine / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000577:Amides; D009829:Oleic Acids; D043562:Receptors, G-Protein-Coupled; D012694:Serine; D048052:Mitogen-Activated Protein Kinase 3