Heparin acts synergistically with interleukin-11 to induce STAT3 activation and in vitro osteoclast formation

Abstract

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 longterm. (Blood. 2002;100:2530-2536)

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

“…In a previous study, we demonstrated that heparin enhances both IL-11-induced STAT3⅐DNA complex formation and transactivation without altering either STAT3 tyrosine or serine 727 phosphorylation (13). In the current study, we confirm these findings and present evidence to support the hypothesis that heparin enhances IL-11-induced STAT3 activation by up-regulating the MAPK pathway.…”

“…By using these models, we showed that heparin causes both a time-and a dosedependent decrease in cancellous bone and that this, in part, results from an increase in osteoclast number and activity (10 -12). In addition, we found that heparin alone has no effect on osteoclast formation, but rather it acts synergistically with interleukin-11 (IL-11), 3 a member of the IL-6 family of cytokines, to enhance both IL-11 signaling and in vitro osteoclast formation (13). When taken together, these findings suggest that IL-11 plays a critical role in the ability of heparin to induce osteoclast formation.…”

“…Previously, we demonstrated that the ability of IL-11 to induce osteoclast formation was enhanced in the presence of heparin even though heparin alone had no effect (13). In addition, we reported that heparin was able to enhance IL-11-induced osteoclast formation, because it acted synergistically with IL-11 to induce the expression of receptor activator of nuclear factor-B ligand (RANKL) on the osteoblast cell surface.…”

“…Previously, we demonstrated that heparin acts synergistically with IL-11, a member of the IL-6 family of cytokines, to enhance both STAT3 activation and in vitro osteoclast formation (13). In the current study, we examine the mechanism by which this synergy occurs.…”

“…Activation-We previously demonstrated that heparin enhances both IL-11-induced STAT3⅐DNA complex formation and transactivation without altering the tyrosine phosphorylation status of STAT3 (13). To further define the mechanism by which this occurs, we pretreated calvaria cells with various serine kinase inhibitors and then assessed, by use of an EMSA, the ability of heparin to promote STAT3⅐DNA complex formation in the presence or absence of IL-11.…”