Oleoyl serine, an endogenous N-acyl amide, modulates bone remodeling and mass

Reem Smoum, Arik Bar, Bo Tan, Garry Milman, Malka Attar-Namdar, Orr Ofek, Jordyn M. Stuart, Alon Bajayo, Joseph Tam, Vardit Kram, David O'Dell, Michael J. Walker, Heather B. Bradshaw, Itai Bab*, Raphael Mechoulam

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

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.

Original languageAmerican English
Pages (from-to)17710-17715
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number41
DOIs
StatePublished - 12 Oct 2010

Keywords

  • Fatty acyl amides

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