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Blood, 1 October 2002, Vol. 100, No. 7, pp. 2530-2536
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Heparin acts synergistically with interleukin-11 to induce STAT3
activation and in vitro osteoclast formation
Kimberly J. Walton,
Joanne
M. Duncan,
Paula Deschamps, and
Stephen G. Shaughnessy
From the Department of Pathology and Molecular
Medicine, McMaster University and the Hamilton Civic Hospitals Research
Center, Hamilton, ON, Canada.
We have previously demonstrated that long-term heparin treatment
causes cancellous bone loss in rats due in part to an increase in the
number of osteoclasts lining the trabecular bone surface. In the
present study, we investigated this phenomenon by examining the
ability of heparin to synergistically enhance interleukin-11 (IL-11)-induced osteoclast formation. Treatment of murine calvaria and
bone marrow cells with IL-11 was found to induce the formation of
tartrate-resistant acid phosphatase-positive (TRAP+)
multinucleated cells (MNCs) in a dose-dependent fashion. No effect was
seen when cocultures were treated with heparin alone. However, when
cocultures were treated with both IL-11 and heparin, IL-11's ability
to induce TRAP+ MNC formation was enhanced 6-fold. In
an attempt to resolve the mechanism responsible for this effect, we
examined the ability of heparin to influence IL-11 signaling using
murine calvaria cells. Heparin was found to enhance both IL-11-induced
STAT3-DNA complex formation and transactivation without altering either STAT3 (signal transducer and activator of transcription-3) tyrosine or
serine phosphorylation. Heparin was also found to enhance IL-11's ability to induce the expression of both receptor activator of nuclear
factor- B ligand (RANKL) and glycoprotein (gp) 130. When taken
together, these findings suggest a plausible mechanism by which heparin
may cause increased osteoclastogenesis and therefore bone loss when
administered long-term.
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