EFFECTS OF LIPOSOME-ENCAPSULATED BISPHOSPHONATES ON ACETYLATED LDL METABOLISM, LIPID-ACCUMULATION AND VIABILITY OF PHAGOCYTING CELLS

Bisphosphonates, the drugs used for the treatment of e.g. osteoporosis , inhibit the development of experimental atherosclerosis. When encaps ulated in liposomes, they also inactivate macrophages, which have a ke y role in atherogenesis. We studied the effects of three clinically us ed bisphosphonates, i.e. clodronate, etidronate and pamidronate, on 1) the viability of mouse peritoneal macrophages and macrophage-like RAW 264 cells, 2) the degradation of I-125-labeled acetylated LDL by RAW 264 cells, and 3) the formation of LDL-derived foam cells in vitro. Li posome-encapsulated clodronate and pamidronate, but not etidronate, de creased the fraction of viable peritoneal macrophages in a concentrati on-dependent manner, whereas RAW 264 cells were much more resistant to the cytotoxic effects of bisphosphonates. Preincubation with liposoma l clodronate and etidronate inhibited in a concentration-dependent man ner the degradation of acetylated LDL in RAW 264 cells, but non-cytoto xic concentrations of liposomal pamidronate had only a weak inhibitory effect. The inhibition was more pronounced by liposomal clodronate th an by liposomal etidronate. At high concentrations (500 mu g protein/m l) of acetylated and aggregated LDL, RAW 264 cells transformed to foam cells. Preincubation with liposomal clodronate and etidronate reduced the cellular accumulation of acetylated LDL-derived lipids, but the d rugs had no effect on the lipid accumulation caused by aggregated LDL. The results suggest that liposomal clodronate and etidronate inhibit the activity of phagocyting cells in internalizing and degrading ather ogenic modified LDL.