Effects of tacrolimus, cyclosporin A and sirolimus on MG63 cells.
The reduction in bone mineral density after organ transplantation results in increased morbidity (post-transplantation bone disease) and remains an unsolved problem. A connection with the long-term application of nonglucocorticoidal immunosuppressants is the subject of controversial discussion. We hypothesized that such substances have an influence on the skeletal system on the cellular level by modulating osteoblast differentiation. Therefore, we investigated the effects of tacrolimus, cyclosporin A and sirolimus as representative substances of nonglucocorticoidal immunosuppressants on cell proliferation and expression of bone tissue-specific genes of human osteoblasts (MG63). None of the examined substances affected cell proliferation, but all influenced the gene expression pattern towards change in cell differentiation. In detail, collagen III and XII, matrix metalloproteinase 2, SMAD2, epithelial growth factor receptor, annexin V and osteonectin expression were increased by all of the examined substances. Tacrolimus, cyclosporin A and sirolimus influence intracellular signalling pathways, transmembranous receptors and bone-specific matrix synthesis. They do not have antiproliferative or toxic effects. We postulate that the shown changes of osteoblast differentiation cause post-transplantation disease.
Krocker
Dörte
D
Center for Musculoskeletal Surgery, Charité, University Medicine Berlin, Berlin, Germany. doerte.krocker@charite.de
Perka
Carsten
C
Tuischer
Jens
J
Funk
Julia
J
Tohtz
Stephan
S
Buttgereit
Frank
F
Matziolis
Georg
G
D015519:Bone Density; D002460:Cell Line; D049109:Cell Proliferation; D016572:Cyclosporine / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D061965:Matrix Metalloproteinase Inhibitors; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D016559:Tacrolimus / Q000494:pharmacology*; D013997:Time Factors
D007166:Immunosuppressive Agents; D061965:Matrix Metalloproteinase Inhibitors; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus