Untersuchung zum Einfluss verschiedener Bisphosphonate auf Zellviabilität und Migrationsfähigkeit von Osteoblastem, Fibroblasten, HUVEC und EPC sowie ihrer Beeinflussung durch Geranyl-Geraniol Substitution
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Philipps-Universität Marburg
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Abstract
Bisphosphonates are osteoanabolic drugs commonly used in the treatment of bone
disseases including malignant bone neoplasia, bone metastasis, muliple myeloma,
Paget´s dissease or osteoprosis. Despite their therapeutical properties one main
side effect is the development of osteonecrosis of the jaw (BP-ONJ). The
pathogenesis of BP-ONJ remains unclear, however it is assumed to be
mulitfactoriell. Although the main mechanism of action of bisphosphonates is the
inhibition of osteoclasts leading to a reduced bony remodelling, extra-sceletall
effects of bisphonsphonates have been published throughout literatur. Regarding
the generations of the bisphosphonate there are two different molecular
mechanisms of action. While first generation bisphosphates like Clodronate induced
their effect by incooperation in an ATP-analoga, recent bisphosphonat generations
inhibit enzymes in the mevalonat pathway. This leads to a reduced activation of
small GTP-binding proteins. The following cellular signaling-pathways are impaired.
The aim of this study was to analyse the impact of four bisphosphonates (Clodronat,
Pamidronat, Ibandronat and Zoledronat) on four different celllines (Osteoblasts,
Fibroblasts, Endothelial Progenitor Cells and Endothel Cells of the human umbilical
cord). Furthermore the influence of geranyl-geraniol substitution should be
investigated.
The data of the present study revealed a significant depressing effect of all four
bisphosphonates on the migration ability of fibroblasts, endothelial progenitor cells
and osteoblasts. The nitrogen containing bisphosphonates (pamidronate,
ibandronate and zoledronate) had furthermore a significant inhibitory impact on
HUVEC. The results of the MTT assay demonstrated a decreased cellviability of
HUVEC of all four bisphosphonates in a 50μM concentration. The bisphosphonates
with increased biological potency (zoledronat, ibandronat) revealed even an
inhibitory effect of cellviability in 5μM concentration. The cellviability of fibroblast
was decreased in the MTT assay in 50μM concentration of clodronate, ibandronate
and zoledronate. All four bisohosphonates showed a depressing effect on
endothelial progenitor cells typical characteristic of colony forming even in a 5μM
concentration.
Geranyl-Geraniol substitution demonstrated an attenute impact on bisphosphonate
effect on all four cell lines. The migration ability of cells of angiogenesis (EPC and
HUVEC) was significantly elevated with geranyl-geraniol subsitution of allbisphosphonates. Geranyl-geraniol substitution led to a significantly improved
migration ability of fibroblasts when added to the bisphosphonates clodronate,
pamidronate and ibandronate. Also a significant increase of migration after geranylgeraniol
substitution could be observed in osteoblasts when pretreated with
ibandronate.
The tests on the viability showed an improvement after geranyl-geraniol subsitution.
The viability of fibroblasts could be significantly increased after geranyl-geraniol
susbstitution when pretreatment with ibandronate in 50μM or 5μM and zoledronate
50μM concentration had been performed. In HUVEC a significantly enhanced
viability could be observed after geranyl-geraniol subsitution in the 50μM clodronate
and 5 and 50μM zoledronate group. The impact on the typical characteristic of EPC
the colony forming property could be significantly improved after geranyl geraniol
subsitution within all four bisphosphonate groups regardsless of the tested
concentrations (5, 25 and 50μM).
Bisphosphonates have an inhibtory effect on the migration ability of all tested cells.
Furthermore they highly influence the cell-viability. Both characterics can be weaked
by the subsitution of geranyl-geraniol. These in vitro findings are a promising
approach for further testing in an in vivo model as a potential local therapeutical
agency against bisphosphonate related osteonecrosis of the jaw.
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Dates
Created: 2019Issued: 2019-06-03Updated: 2019-06-06
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
DFG-subjects
ZellviabilitätMigrationsfähigkeitGeranyl GeraniolBisphosphonate
DDC-Numbers
610
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Lux, Christine: Untersuchung zum Einfluss verschiedener Bisphosphonate auf Zellviabilität und Migrationsfähigkeit von Osteoblastem, Fibroblasten, HUVEC und EPC sowie ihrer Beeinflussung durch Geranyl-Geraniol Substitution. : Philipps-Universität Marburg 2019-06-03. DOI: https://doi.org/10.17192/z2019.0301.
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This item has been published with the following license: In Copyright