TY - JOUR
T1 - Effects of immunosuppressants on receptor activator of NF-κB ligand and osteoprotegerin production by human osteoblastic and coronary artery smooth muscle cells
AU - Hofbauer, Lorenz C.
AU - Shui, Chaoxiang
AU - Riggs, B. Lawrence
AU - Dunstan, Colin R.
AU - Spelsberg, Thomas C.
AU - O'Brien, Timothy
AU - Khosla, Sundeep
N1 - Funding Information:
The authors acknowledge the excellent technical assistance of Ms. Marcy J. Schroeder, Ms. Roberta A. Soderberg, Ms. Bethany Ngo, and Ms. Manuela Kauss. This work was supported by Grant AG-04875 from the National Institutes of Health (to Dr. Khosla) and a research grant from Deutsche Forschungsgemeinschaft (Ho 1875/ 2-1) (to Dr. Hofbauer).
PY - 2001
Y1 - 2001
N2 - Osteoporosis and vasculopathy are common after organ transplantation and have been largely attributed to the use of immununosuppressants. Osteoprotegerin (OPG) is produced by osteoblastic and arterial cells, and inhibits osteoclast functions by neutralizing receptor activator of NF-κB 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.
AB - Osteoporosis and vasculopathy are common after organ transplantation and have been largely attributed to the use of immununosuppressants. Osteoprotegerin (OPG) is produced by osteoblastic and arterial cells, and inhibits osteoclast functions by neutralizing receptor activator of NF-κB 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.
KW - Cyclosporine A
KW - Osteoblasts
KW - Osteoprotegerin
KW - Rapamycin
KW - Smooth muscle cell
KW - Stromal cell
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U2 - 10.1006/bbrc.2000.4130
DO - 10.1006/bbrc.2000.4130
M3 - Article
C2 - 11162519
AN - SCOPUS:0034817070
SN - 0006-291X
VL - 280
SP - 334
EP - 339
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 1
ER -