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Liposomes containing phosphatidylserine (PS) are engulfed by phagocytes including macrophages, microglia, and dendritic cells. PS liposomes (PSLs) mimic the effects of apoptotic cells on these phagocytes to induce the secretion of anti-inflammatory molecules and to inhibit the maturation of dendritic cells. However, the effects of PSLs on osteoclasts, which are also differentiated from the common myeloid precursors, remain to be determined. This study investigated the effects of PSLs on the osteoclastogenesis. In the rat bone marrow culture system, osteoclast precursors phagocytosed PSLs to secrete TGF-β1 and PGE2, which in turn inhibited osteoclastogenesis through the downregulation of receptor activator for NF-κB ligand, receptor activator of NF-κB, ICAM-1, and CD44. Consistent with these in vitro observations, i.m. injection of PSLs significantly increased the plasma level of TGF-β1 and PGE2 and decreased the expression of receptor activator for NF-κB ligand, receptor activator of NF-κB, and ICAM-1 in the skeletal tissues of ankle joints of rats with adjuvant arthritis (AA). A quantitative analysis using microcomputed tomography revealed that PSLs as well as TGF-β1 together with PGE2 significantly inhibited AA-induced trabecular bone loss. These observations strongly suggest that PSLs generate TGF-β1 and PGE2 release, leading to inhibit osteoclastogenesis and AA-induced trabecular bone loss. Because PS is a component of the cell membrane, PSLs therefore can be a potentially effective pharmacological intervention against abnormal bone loss, such as osteoporosis without deleterious side effects.

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-b1 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)-1b-producing to IL-10-producing cells after the phagocytosis of PSLs. In lipopolysaccharide (LPS)-stimulated macrophages, PSLs also significantly decreased IL-1b production, but increased IL-10 production. Moreover, PSLs inhibited the rapid activation of p38 mitogen-activated protein kinases (MAPK) and nuclear factor (NF)-kB, 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-kB (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;

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