Heparin acts synergistically with interleukin-11 to induce STAT3 activation and in vitro osteoclast formation.
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-kappaB 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.
Walton
Kimberly J
KJ
Department of Pathology and Molecular Medicine, McMaster University and the Hamilton Civic Hospitals Research Center, Hamilton, ON, Canada.
Duncan
Joanne M
JM
Deschamps
Paula
P
Shaughnessy
Stephen G
SG
D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D015152:Blotting, Northern; D001854:Bone Marrow Cells / Q000166:cytology* / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004357:Drug Synergism; D005260:Female; D006493:Heparin / Q000494:pharmacology*; D017370:Interleukin-11 / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010710:Phosphates / Q000378:metabolism; D010766:Phosphorylation; D011247:Pregnancy; D050796:STAT3 Transcription Factor; D012886:Skull / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism*
D000209:Acute-Phase Proteins; D004268:DNA-Binding Proteins; D017370:Interleukin-11; D010710:Phosphates; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D006493:Heparin