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Regulation of thrombopoietin levels by c-mpl-mediated binding to platelets
PJ Fielder, AL Gurney, E Stefanich, M Marian, MW Moore, K Carver-Moore and FJ de Sauvage
Departments of Molecular Oncology, Genentech Inc, South San Francisco, CA
USA.
The involvement of platelets and the c-mpl receptor in the regulation of
thrombopoietin (TPO) plasma concentrations and tissue mRNA levels was
investigated in both normal mice and mice defective in c-mpl (c-mpl- /-).
Although c-mpl-/- mice have fewer platelets and higher plasma TPO activity
than normal mice, there was no increase in TPO mRNA levels as measured by
an S1 nuclease protection assay. After the intravenous injection of
125I-TPO, specific uptake of radioactivity by the spleen and blood cells
was present in the normal mice, but absent in the c-mpl- /- mice.
Platelet-rich plasma (PRP) from normal mice was able to bind and
internalize 125I-TPO, whereas PRP from c-mpl-/- mice lacked this ability.
Analysis of 125I-TPO binding to normal PRP indicated that binding was
specific and saturable, with an approximate affinity of 560 pmol/L and 220
receptors per platelet. PRP from normal mice was also able to degrade
125I-TPO into lower molecular weight fragments. After the intravenous
injections, c-mpl-/- mice cleared a dose of 125I-TPO at a much slower rate
than did normal mice. Injection of washed platelets from normal mice into
c-mpl-/- mice resulted in a dramatic, but transient, decrease in plasma TPO
levels. These data provide evidence that platelets regulate plasma TPO
levels via binding to the c-mpl receptor on circulating platelets.
Volume 87,
Issue 6,
pp. 2154-2161,
03/15/1996
Copyright © 1996 by The American Society of Hematology
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