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

Lorenz C. Hofbauer, Chaoxiang Shui, B. Lawrence Riggs, Colin R. Dunstan, Thomas C. Spelsberg, Timothy O'Brien, Sundeep Khosla

Research output: Contribution to journalArticle

185 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)334-339
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume280
Issue number1
DOIs
StatePublished - Jan 1 2001

Keywords

  • Cyclosporine A
  • Osteoblasts
  • Osteoprotegerin
  • Rapamycin
  • Smooth muscle cell
  • Stromal cell

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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