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J. Biol. Chem., Vol. 281, Issue 30, 20780-20787, July 28, 2006

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Heparin Synergistically Enhances Interleukin-11 Signaling through Up-regulation of the MAPK Pathway^*

From the Departments of Pathology and Molecular Medicine and Medicine, McMaster University and the Henderson Research Centre, Hamilton, Ontario L8V 1C3, Canada

Using an animal model of heparin-induced osteoporosis we previously demonstrated that heparin causes bone loss, in part, by increasing osteoclast number and activity. Furthermore, we found that, although heparin alone has no effect, it is able to synergistically enhance Interleukin-11 (IL-11)-induced signal transducer and activator of transcription 3 (STAT3) activation and thus increase osteoclast formation in vitro. In the present study, we examine the effect of various serine kinase inhibitors on the ability of heparin to act synergistically with IL-11. Inhibition of the c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), or the phosphatidylinositol 3-kinase pathways had no effect on the ability of heparin to promote either IL-11-induced STAT3·DNA complex formation or osteoclast formation in vitro. In contrast, PD098059, a MAPK kinase inhibitor, completely abolished the synergy between heparin and IL-11. In an attempt to resolve the mechanism by which this was occurring, we examined the effect of heparin on STAT3 Ser-727 phosphorylation and extracellular signal-regulated kinases 1 and 2 (Erk1/2) activation, either in the presence or absence of IL-11. Heparin alone was found to have no effect on Ser-727 phosphorylation, nor did heparin alter the phosphorylation status of Ser-727 in the presence of IL-11. Heparin was, however, found to increase Erk1/2 activation in both a time- and dose-dependent manner. When taken together, these findings suggest that heparin enhances IL-11-induced STAT3 activation and thus osteoclast formation, by a mechanism that is independent of STAT3 Ser-727 phosphorylation but that involves up-regulation of the MAPK pathway.

Received for publication, January 6, 2006 , and in revised form, April 26, 2006.

^* This work was supported in part by the Canadian Institutes of Health Research (CIHR) (Grant MOP-5333 to S. G. S.) and a CIHR Team Grant In Venous Thromboembolism (Grant FRN79846). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ A Career Investigator of the Heart and Stroke Foundation of Ontario (HSFO) and holder of a Canada Research Chair in Thrombosis and the HSFO/J. F. Mustard Chair in Cardiovascular Research.

² To whom correspondence should be addressed: Henderson Research Centre, 711 Concession St., Hamilton, Ontario L8V 1C3, Canada. Tel.: 905-527-2299 (ext. 43778); Fax: 905-575-2646; E-mail: sshaughnessy{at}thrombosis.hhscr.org.

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