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

被引:186
作者
Hofbauer, LC
Shui, CX
Riggs, BL
Dunstan, CR
Spelsberg, TC
O'Brien, T
Khosla, S
机构
[1] Mayo Clin & Mayo Fdn, Endocrine Res Unit, Rochester, MN 55905 USA
[2] Mayo Clin & Mayo Fdn, Dept Biochem & Mol Biol, Rochester, MN 55905 USA
[3] Amgen Inc, Thousand Oaks, CA 91320 USA
关键词
cyclosporine A; osteoblasts; osteoprotegerin; rapamycin; stromal cell; smooth muscle cell;
D O I
10.1006/bbrc.2000.4130
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 OPC: 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 60 cause vascular disease. (C) 2001 Academic Press.
引用
收藏
页码:334 / 339
页数:6
相关论文
共 32 条
[1]   A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function [J].
Anderson, DM ;
Maraskovsky, E ;
Billingsley, WL ;
Dougall, WC ;
Tometsko, ME ;
Roux, ER ;
Teepe, MC ;
DuBose, RF ;
Cosman, D ;
Galibert, L .
NATURE, 1997, 390 (6656) :175-179
[2]   ATHEROGENIC EFFECTS OF CYCLOSPORINE IN AN EXPERIMENTAL-MODEL OF ARTERIAL AUTOGRAFT [J].
BELLON, JM ;
BUJAN, MJ ;
JURADO, F ;
HERNANDO, A ;
GHONDUVILLA, N ;
DOMINGUEZ, B ;
CONTRERAS, L .
TRANSPLANTATION, 1995, 60 (05) :407-414
[3]   osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification [J].
Bucay, N ;
Sarosi, I ;
Dunstan, CR ;
Morony, S ;
Tarpley, J ;
Capparelli, C ;
Scully, S ;
Tan, HL ;
Xu, WL ;
Lacey, DL ;
Boyle, WJ ;
Simonet, WS .
GENES & DEVELOPMENT, 1998, 12 (09) :1260-1268
[4]   THE DELETERIOUS EFFECTS OF LONG-TERM CYCLOSPORINE-A, CYCLOSPORINE-G, AND FK506 ON BONE-MINERAL METABOLISM IN-VIVO [J].
CVETKOVIC, M ;
MANN, GN ;
ROMERO, DF ;
LIANG, XG ;
MA, YF ;
JEE, WSS ;
EPSTEIN, S .
TRANSPLANTATION, 1994, 57 (08) :1231-1237
[5]   Cyclosporine, but not FK506, selectively induces renal and coronary artery smooth muscle contraction [J].
Epstein, A ;
Beall, A ;
Wynn, J ;
Mulloy, L ;
Brophy, CM .
SURGERY, 1998, 123 (04) :456-460
[6]  
Epstein S, 1996, J BONE MINER RES, V11, P1
[7]   CYCLOSPORINE A - FRIEND OR FOE [J].
EPSTEIN, S .
CALCIFIED TISSUE INTERNATIONAL, 1991, 49 (04) :232-234
[8]  
FERNS G, 1990, AM J PATHOL, V137, P403
[9]   The expression of osteoprotegerin and RANK ligand and the support of osteoclast formation by stromal-osteoblast lineage cells is developmentally regulated [J].
Gori, F ;
Hofbauer, LC ;
Dunstan, CR ;
Spelsberg, TC ;
Khosla, S ;
Riggs, BL .
ENDOCRINOLOGY, 2000, 141 (12) :4768-4776
[10]  
HARRIS SA, 1995, J BONE MINER RES, V10, P178