Glycobiology, Vol 8, 1149-1155, Copyright © 1998 by Society for Glycobiology
J Malmstrom and G Westergren-Thorsson
Heparan sulfate is a molecule that possesses a large structural variability
and which has been shown to inhibit the proliferation of fibroblasts in
vitro. The aim of this study was to determine whether the
anti-proliferative effects of heparan sulfate were exerted by regulation of
the activity of the platelet-derived growth factor and/or of the
platelet-derived growth factor receptors. Both l-iduronate-rich,
anti-proliferative and the l-iduronate-poor, non-anti-proliferative heparan
sulfate species, were incubated with confluent human embryonic lung
fibroblasts for 24 h. The mRNA levels for PDGF-AA, PDGF-BB, and their
receptors were measured. Binding studies were performed with [125I]-PDGF-BB
and [125I]-EGF for 2 h at 4 degreesC in cultures preincubated with both
types of heparan sulfate for 24 h. In separate experiments, cultures were
incubated together with heparan sulfate and [125I]-PDGF-BB for 2 h at 4
degreesC. Increases of two- to threefold in the mRNA levels for both the
alpha- and the beta-receptors of PDGF was obtained after treatment with
both types of heparan sulfate, whereas the mRNA levels of both the PDGF-AA
and the PDGF-BB were essentially unaffected. A sixfold increase in binding
was only noted for [125I]- PDGF-BB in cultures pre-treated with the
anti-proliferative heparan sulfate for 24 h, whereas no effect was noted
with use of the non-anti- proliferative heparan sulfate. Incubating the
[125I]-PDGF-BB and the anti-proliferative heparan sulfate together for 2 h
resulted in a smaller, threefold increase in binding. This indicates that
the anti- proliferative heparan sulfate both stabilizes and increases
expression of the PDGF receptors. To investigate whether the increased
number of PDGF receptors could affect cell activity, cells were
preincubated with anti-proliferative heparan sulfate and then treated with
PDGF-BB. This resulted in an increase in mitogenicity compared to cells
treated only with PDGF-BB. Neither an increase in binding for [125I-EGF]
nor an increase in the mitogenic response of EGF could be observed in
cultures pre-treated with the anti-proliferative heparan sulfate. The
results indicate that the extracellular matrix itself may regulate
important biological phenomena such as cell proliferation and matrix
production through affecting the expression of receptors of PDGF, which
initiate both stimulatory and inhibitory signals.
ORIGINAL ARTICLES
Heparan sulfate upregulates platelet-derived growth factor receptors on human lung fibroblasts
Department of Cell and Molecular Biology, Lund University, Sweden.
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