| 概要 |
Liposomes containing phosphatidylserine (PS) are engulfed by phagocytes including macrophages, microglia and dendritic cells. PS liposomes mimic the effects of apoptotic cells on these phagocytes to i...nduce the secretion of antiinflammatory molecules and to inhibit the maturation of dendritic cells. Thus, the interplay between PS liposomes and phagocytes seem to create a microenvironment that can suppress immune and inflammatory responses. However, the effects of PS liposomes on osteoclasts, which are also differentiated from the common myeloid precursors, and the inflammatory bone loss are unknown. In chapter I of the present study， the direct effects of PS liposomes on the osteoclastogenesis were investigated. In the rat bone marrow culture system, osteoclast precursors phagocytozed PS liposomes to secrete transforming growth factor (TGF) b1 and prostaglandin (PG) E2, which in turn inhibited osteoclastogenesis through the down-regulation of receptor activator for NF-kB ligand (RANKL), receptor activator of NF-kB (RANK), intercellular adhesion molecule-1 (ICAM-1) and CD44. In consistence with these in vitro observations, intramuscular injection of PS liposomes significantly increased the plasma level of TGF-b1 and PGE2 and decreased the expression of RANKL, RANK and ICAM-1 in the skeletal tissues of ankle joints of adjuvant arthritis (AA) rats. A quantitative analysis using micro computed tomography revealed that PS liposomes as well as TGF-b1 together with PGE2 significantly inhibited AAinduced trabecular bone loss. In chapter II of the present study, the effects of PS liposomes on the phenotypic change of infiltrated macrophages, which were considered indirectly inhibiting osteoclastogenesis during inflammatory bone loss, were elucidated. In the ankle joints of AA rats, approximately half of the infiltrated macrophages 1 underwent a phenotypic change from interleukin (IL)-1b-producing to IL-10- producing cells after the phagocytosis of PS iposomes. In lipopolysaccharide (LPS)-stimulated macrophages, PS liposomes significantly decreased the IL-1b production, but increased the IL-10 production. Moreover, PS liposomes inhibited the rapid activation of p38 mitogen-activated protein kinases (MAPK) and NF-kB, but enhanced the delayed activation of extracellular signal-regulated kinase (ERK) in LPS-stimulated macrophages. The differential of PSL-induced influences on the activities of p38 MAPK and ERK is a likely underlying mechanism for phenotypic change of infiltrated macrophages after the phagocytosis of PS liposomes. This phenotypic change may be responsible for a significant decrease in the mean mRNA level of RANK and RANKL in the ankle joint of PS liposome-treated AA rats, resulting in the inhibition of inflammatory bone loss. In conclusions, these observations strongly suggest that phagocytosis of PS liposomes can strongly inhibit AA-induced bone loss through both the direct inhibitory effects on osteoclastogenesis and the indirect effects on changing the infiltrated macrophages from pro-inflammatory to anti-inflammatory phenotype. Therefore ， PS liposomes may be potentially useful for achieving pharmacological intervention against inflammatory bone loss in many diseases such as rheumatoid arthritis (RA) and periodontitis without any apparent deleterious side effects.続きを見る
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