Background and purpose:
The inflammation-resolving lipid mediator resolvin E1 (RvE1) effectively stops inflammation-induced bone loss in vivo in experimental periodontitis. It was of interest to determine whether RvE1 has direct actions on osteoclast (OC) development and bone resorption.
Primary OC cultures derived from mouse bone marrow were treated with RvE1 and analysed for OC differentiation, cell survival and bone substrate resorption. Receptor binding was measured using radiolabelled RvE1. Nuclear factor (NF)-κB activation and Akt phosphorylation were determined with western blotting. Lipid mediator production was assessed with liquid chromatography tandem mass spectrometry.
OC growth and resorption pit formation were markedly decreased in the presence of RvE1. OC differentiation was inhibited by RvE1 as demonstrated by decreased number of multinuclear OC, a delay in the time course of OC development and attenuation of receptor activator of NF-κB ligand-induced nuclear translocation of the p50 subunit of NF-κB. OC survival and apoptosis were not altered by RvE1. Messenger RNA for both receptors of RvE1, ChemR23 and BLT1 is expressed in OC cultures. Leukotriene B4 (LTB4) competed with [3H]RvE1 binding on OC cell membrane preparations, and the LTB4 antagonist U75302 prevented RvE1 inhibition of OC growth, indicating that BLT1 mediates RvE1 actions on OC. Primary OC synthesized the RvE1 precursor 18R-hydroxy-eicosapentaenoic acid and LTB4. Co-incubation of OC with peripheral blood neutrophils resulted in transcellular RvE1 biosynthesis.
Conclusions and implications:
These results indicate that RvE1 inhibits OC growth and bone resorption by interfering with OC differentiation. The bone-sparing actions of RvE1 are in addition to inflammation resolution, a direct action in bone remodelling.
British Journal of Pharmacology (2008) 155, 1214–1223; doi:10.1038/bjp.2008.367; published online 22 September 2008