Effects of immunosuppressants on receptor activator of NF-kappa B ligand and osteoprotegerin production by human osteoblastic and coronary artery smooth muscle cells

Osteoporosis and vasculopathy are common after organ transplantation and ha ve been largely attributed to the use of immunosuppressants. Osteoprotegeri n (OPG) is produced by osteoblastic and arterial cells, and inhibits osteoc last functions by neutralizing receptor activator of NF-kappaB ligand (RANK L). Because OPG-deficient mice develop osteoporosis and arterial calcificat ion, we assessed the effects of immunosuppressants on OPG and RANKL express ion by human osteoblastic and coronary artery smooth muscle cells (CASMC). Cyclosporine A, rapamycin, and FK-506 decreased OPG mRNA and protein levels in undifferentiated marrow stromal cells (by 63, 44, and 68%, respectively , P < 0.001). All three immunosuppressants increased RANKL mRNA levels in t hese cells by 60 to 210%. In contrast to these effects on marrow stromal ce lls, rapamycin, which may be relatively bone-sparing, increased OPG mRNA an d protein production (by 120%, P < 0.001) in mature osteoblastic cells. Cyc losporine A also decreased OPG mRNA and protein production (by 52%, P < 0.0 01) of CASMC. In conclusion, immunosuppressants decrease OPC: mRNA and prot ein production and increase RANKL gene expression by marrow stromal cells, and cyclosporine suppresses OPG production in CASMC. These studies thus pro vide a potential mechanism for immunosuppressant-induced bone loss, and the propensity of cyclosporine A 60 cause vascular disease. (C) 2001 Academic Press.