Effects of tacrolimus, cyclosporin A and sirolimus on MG63 cells

Abstract

Summary 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.

FGF-23 Levels before and after Renal Transplantation

“…In patients with chronic renal failure and secondary hyperparathyroidism that have undergone renal transplantation, it is expected that there is a greater production in the first trimester after transplantation, until osteoblasts become inactive and bone metabolism is suppressed. It has been reported that corticosteroids, calcineurin inhibitors, and mTOR inhibitors stimulate FGF-23 production [9, 10], even though in the first months after transplantation, with the use of higher doses of these drugs we as well as others observed the greater reduction [3–6]. Furthermore, hypophosphatemia which is the major stimulant for FGF-23 secretion is resolved.…”

mTOR Inhibitors (Rapamycin and its Derivatives) and Nitrogen Containing Bisphosphonates: Bi-Functional Compounds for the Treatment of Bone Tumours

“…Similarly to NRapamycin and derivatives (excepted tacrolimus) also influence bone tissues. Indeed, mTOR appears as an essential signalling pathway engaged in the stimulation of osteoclast survival [79] and affects osteoblast differentiation [80]. Tumour Necrosis Factor-α (TNF-α), Receptor Activator of Nuclear Factor κB Ligand (RANKL) and Macrophage-Colony Stimulating Factor (M-CSF) promote osteoclast survival by signalling through mTOR/S6K [70].…”

Fibroblast Growth Factor-23—A Potential Uremic Toxin

“…Finally, it should be noted that successful kidney transplantation usually tends to lower the markedly increased FGF23 concentrations so often seen in advanced stages of CKD [74,75,76,77]. The results of some clinical studies suggest that despite the rapid decline in plasma FGF23 concentration after kidney transplantation, it is still slightly but significantly higher than in the general population [77].…”

“…The results of some clinical studies suggest that despite the rapid decline in plasma FGF23 concentration after kidney transplantation, it is still slightly but significantly higher than in the general population [77]. This could be attributed to the common use of phosphate supplementation or active vitamin D treatment of the post-transplant hypophosphatemia [74,78], but may also be related to the observations that calcineurin inhibitors and sirolimus in fact stimulate FGF23 production [75,76]. On the other hand, no differences in the plasma concentration of FGF23 between the post-transplant and CKD population with equal eGFR have been found [74].…”