Phosphatidylserine-containing liposomes suppress inflammatory bone loss by ameliorating the cytokine imbalance provoked by infiltrated macrophages

Phosphatidylserine (PS)-containing liposomes (PSLs) strongly inhibit inflammatory bone loss in adjuvant arthritic (AA) rats. This effect was attributed to the inhibition of osteoclastogenesis through the secretion of prostaglandin E-2 and transforming growth factor-beta 1 by osteoclast precursors after the phagocytosis of PSLs. However, infiltrated macrophages are considered to secrete anti-inflammatory mediators after phagocytosis of PSLs, which also contribute to inhibiting osteoclastogenesis. In the present study, we have attempted to elucidate the effects of PSLs on the phenotype of infiltrated macrophages during inflammatory bone loss. In AA rats, the ankle joints swelled with the infiltration of both macrophages and helper T cells into the synovium after a complete Freund's adjuvant injection. In the ankle joints of AA rats, approximately half of the infiltrated macrophages underwent a phenotypic change from interleukin (IL)-1 beta-producing to IL-10-producing cells after the phagocytosis of PSLs. In lipopolysaccharide (LPS)-stimulated macrophages, PSLs also significantly decreased IL-1 beta production, but increased IL-10 production. Moreover, PSLs inhibited the rapid activation of p38 mitogen-activated protein kinases (MAPK) and nuclear factor (NF)-kappa B, but enhanced the delayed activation of extracellular signal-regulated kinase (ERK) in LPS-stimulated macrophages. PSL-induced different influence on the activities of p38 MAPK and ERK is a likely underlying mechanism for phenotypic change of infiltrated macrophages after the phagocytosis of PSLs. This phenotypic change may be responsible for a significant decrease in the mean mRNA level of the receptor activator of NF-kappa B (RANK) and the RANK ligand (RANKL) in the ankle joint of PSL-treated AA rats, resulting in the inhibition of inflammatory bone loss. Laboratory Investigation (2011) 91, 921-931; doi:10.1038/labinvest.2011.54; published online 4 April 2011