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@PHDTHESIS{Bergmann:59440,
author = {Bergmann, Markus},
othercontributors = {Lorenzen, Johann},
title = {{O}steolyse beim {M}ultiplen {M}yelom : {U}ntersuchungen am
{Z}ellmodell},
address = {Aachen},
publisher = {Publikationsserver der RWTH Aachen University},
reportid = {RWTH-CONV-121225},
pages = {IX, 73 S. : Ill., graph. Darst.},
year = {2005},
note = {Aachen, Techn. Hochsch., Diss., 2005},
abstract = {Myeloma is characterized by bone disease leading to severe
bone pain and pathologic fractures. Only over the last few
years the biochemistry of osteolysis in multiple myeloma has
become clearer. A basic cytokine network responsible for
balancing ostgenesis and osteolysis has been described
consisting of a receptor called receptor activator of NF-?B
(RANK), its ligand (RANKL) and the soluble decoy receptor
osteoprotegerin (OPG). Binding of RANKL to RANK leads to
osteoclastogenesis and osteolysis whereas binding to OPG
inactivates RANKL. Myeloma cells seem to disturb bone marrow
microenvironment in a manner tipping the balance towards
osteolysis. On one hand syndecan 1 (SDC1), a transmembrane
heparan sulfate proteoglycan on myeloma cells, is able to
sequester OPG and to mediate internalization and degradation
of OPG in myeloma cells. On the other hand, myeloma cells
are thought to imbalance the OPG/RANKL system by influencing
bone marrow stromal cells, the major source of OPG and RANKL
in bone marrow microenvironment. This thesis presents a
sufficient procedure for investigating expression of OPG,
RANKL and SDC1 on the mRNA level based on semiquantitative
realtime RT-PCR. Using this method we show that treatment of
human foreskin fibroblasts with myeloma cell contitioned
media and fibroblast/myeloma cell coculture both lead to a
significant decrease in expression of OPG mRNA in
fibroblasts. These data indicate that myeloma cells
influence OPG expression in fibroblasts as a model for bone
marrow stromal cells and, thus, disrupt RANKL/OPG cytokine
axis to trigger bone destruction. In contrast to the
published literature, this happens through a soluble factor
as demonstrated by the conditioned media experiments.
Moreover fibroblasts and U-266 both are negative for RANKL
even if grown in coculture. The levels of SDC1 mRNA in
myeloma cell lines U-266 and IM-9 are not affected by
enhancing the autocrine IL-6 loop or by enhancing or
interrupting the autocrine IL-15 loop. Furthermore treatment
of U-266 with fibroblast conditioned media or myeloma
cell/fibroblast coculture does not alter expression of SDC1
mRNA significantly. A polarized expression of SDC1 protein
on U-266 cell surface can be confirmed by immune
fluorescence staining. Cytokine and contactmediated
interactions between myeloma cells and mesenchymal cells
shift the balance towards osteolysis within the
microenvironment of myeloma infiltrates. Disruption of the
OPG/RANKL cytokine axis seems to be of major importance.
Expression of SDC1 by myeloma cells is not affected by
mesenchymal cells and is independent of IL-6 or IL-15
autocrine loop.},
cin = {510000-1},
ddc = {610},
cid = {$I:(DE-82)510000-1_20140620$},
typ = {PUB:(DE-HGF)11},
urn = {urn:nbn:de:hbz:82-opus-11269},
url = {https://publications.rwth-aachen.de/record/59440},
}
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