Effects of immunosuppressants on receptor activator of NF-kappaB ligand and osteoprotegerin production by human osteoblastic and coronary artery smooth muscle cells.
Osteoporosis and vasculopathy are common after organ transplantation and have been largely attributed to the use of immunosuppressants. Osteoprotegerin (OPG) is produced by osteoblastic and arterial cells, and inhibits osteoclast functions by neutralizing receptor activator of NF-kappaB ligand (RANKL). Because OPG-deficient mice develop osteoporosis and arterial calcification, we assessed the effects of immunosuppressants on OPG and RANKL expression 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 these cells by 60 to 210%. In contrast to these effects on marrow stromal cells, rapamycin, which may be relatively bone-sparing, increased OPG mRNA and protein production (by 120%, P < 0.001) in mature osteoblastic cells. Cyclosporine A also decreased OPG mRNA and protein production (by 52%, P < 0.001) of CASMC. In conclusion, immunosuppressants decrease OPG mRNA and protein production and increase RANKL gene expression by marrow stromal cells, and cyclosporine suppresses OPG production in CASMC. These studies thus provide a potential mechanism for immunosuppressant-induced bone loss, and the propensity of cyclosporine A to cause vascular disease.
Hofbauer
L C
LC
Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota 55905, USA.
Shui
C
C
Riggs
B L
BL
Dunstan
C R
CR
Spelsberg
T C
TC
O'Brien
T
T
Khosla
S
S
D001854:Bone Marrow Cells / Q000166:cytology; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D005333:Fetus; D005786:Gene Expression Regulation / Q000187:drug effects; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger / Q000235:genetics; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*
D002352:Carrier Proteins; D006023:Glycoproteins; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus