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

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. 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. Osteoporosis is a well recognized complication of long term heparin therapy (1Pettila V. Leinonen P. Markkola A. Hiilesmaa V. Kaaja R. Thromb. Haemost. 2002; 87: 182-186Crossref PubMed Scopus (237) Google Scholar, 2Dahlman T.C. Sjoberg H.E. 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Gynecol. 1993; 168: 1265-1270Abstract Full Text PDF PubMed Scopus (354) Google Scholar). However, little is known about the mechanism by which heparin causes bone loss. To address this issue we developed several in vitro and in vivo models with which to study the effects of heparin on bone. By using these models, we showed that heparin causes both a time- and a dose-dependent decrease in cancellous bone and that this, in part, results from an increase in osteoclast number and activity (10Muir J. Andrew M. Hirsh J. Weitz J.I. Young E. Deschamps P. Shaughnessy S.G. Blood. 1996; 88: 1314-1320Crossref PubMed Google Scholar, 11Muir J.M. Hirsh J. Weitz J.I. Andrew M. Young E. Shaughnessy S.G. Blood. 1997; 89: 3236-3242Crossref PubMed Google Scholar, 12Shaughnessy S.G. Hirsh J. Bhandari M. Muir J.M. Young E. Weitz J.I.A. Blood. 1999; 93: 1231-1236Crossref PubMed Google Scholar). In addition, we found that heparin alone has no effect on osteoclast formation, but rather it acts synergistically with interleukin-11 (IL-11), 3The abbreviations used are: IL-11, interleukin-11; gp, glycoprotein; Jak, Janus tyrosine kinase; STAT, signal transducer and activator of transcription; MAPK, mitogen-activate protein kinase; α-MEM, α-minimal essential medium; FBS, fetal bovine serum; EMSA, electrophoretic mobility shift assay; SIE, serum inducible element; Erk, extracellular signal-regulated kinase; MEK, MAPK/Erk kinase; RANKL, receptor activator of nuclear factor-κB ligand; siRNA, small interference RNA; TRAP, tartrate-resistant acid phosphatase; JNK, c-Jun N-terminal kinase; MNC, multinucleated cell. a member of the IL-6 family of cytokines, to enhance both IL-11 signaling and in vitro osteoclast formation (13Walton K.J. Duncan J.M. Deschamps P. Shaughnessy S.G. Blood. 2002; 100: 2530-2536Crossref PubMed Scopus (39) Google Scholar). When taken together, these findings suggest that IL-11 plays a critical role in the ability of heparin to induce osteoclast formation. This finding may account for the increase in bone resorption that we observe in our animal models of heparin-induced osteoporosis. IL-11 belongs to a family of cytokines that includes IL-6, leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and cardiotrophin-1 (14Paul S.R. Bennett F. Calvetti J.A. Kelleher K. Wood C.R. O'Hare R.M. Leary A.C. Sibley B. Clark S.C. Williams D.A. Yang Y.C. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 7512-7516Crossref PubMed Scopus (567) Google Scholar). All members of this family display multiple effects on both hematopoietic and nonhematopoietic cell populations, and as such, are known to stimulate osteoclast formation both in vitro and in vivo (15Girasole G. Passeri G. Jilka R.L. Manolagas S.C. J. Clin. Invest. 1994; 93: 1516-1524Crossref PubMed Scopus (364) Google Scholar, 16Elias J.A. Tang W. Horowitz M.C. Endocrinology. 1995; 136: 489-498Crossref PubMed Google Scholar, 17Romas E. Udagawa N. Zhou H. Tamura T. Saito M. Taga T. Hilton D.J. Suda T. Ng K.W. Martin T.J. J. Exp. Med. 1996; 183: 2581-2591Crossref PubMed Scopus (176) Google Scholar, 18O'Brien C.A. Lin S.C. Bellido T. Manolagas S.C. J. Cell. Biochem. 2000; 79: 532-541Crossref PubMed Scopus (39) Google Scholar). Receptors for these cytokines are found on the osteoblast cell surface where they initiate signal transduction through a series of well defined steps. Thus, following binding to their respective α-chain receptors these cytokines form a tri-molecular complex with glycoprotein (gp)130 and initiate signal transduction through activation of the Janus family of tyrosine kinases (Jak1, Jak2, and Tyk2) (19Kishimoto T. Taga T. Akira S. Cell. 1994; 76: 253-262Abstract Full Text PDF PubMed Scopus (1250) Google Scholar, 20Stahl N. Boulton T.G. Farruggella T. Ip N.Y. Davis S. Witthuhn B.A. Quelle F.W. Silvennoinen O. Science. 1994; 263: 92-95Crossref PubMed Scopus (849) Google Scholar). This activation results in the phosphorylation of gp130 at specific tyrosine residues located within its cytoplasmic domain and creates a docking site for members of the signal transducer and activator of transcription (STAT) family (20Stahl N. Boulton T.G. Farruggella T. Ip N.Y. Davis S. Witthuhn B.A. Quelle F.W. Silvennoinen O. Science. 1994; 263: 92-95Crossref PubMed Scopus (849) Google Scholar). Once STATs (STAT3 and STAT1) bind to gp130, they are also phosphorylated on specific tyrosine residues by Jak. Following phosphorylation, STATs form homo- or heterodimers and translocate into the nucleus where they act to promote transcription by binding to specific promoter elements within their various response genes (21Heinrich P.C. Behrmann I. Müller-Newen G. Schaper F. Graeve L. Biochem. J. 1998; 334: 297-314Crossref PubMed Scopus (1757) Google Scholar). Although tyrosine phosphorylation of STATs (i.e. Tyr-705) is a necessary prerequisite for the dimerization and subsequent binding of STATs to DNA, STAT activity can also be influenced by serine phosphorylation (22Zhong Z. Wen Z. Darnell Jr., J. Science. 1994; 264: 95-98Crossref PubMed Scopus (1735) Google Scholar, 23Lütticken C. Wegenka U.M. Yuan J. Buschmann J. Schindler C. Ziemiecki A. Harpur A.G. Wilks A.F. Yasukawa K. Taga T. Kishimoto T. Barbieri G. Pellegrini S. Sendtner M. Heinrich P.C. Horn F. Science. 1994; 263: 89-92Crossref PubMed Scopus (713) Google Scholar, 24Narazaki M. Witthuhn B.A. Yoshida K. Silvennoinen O. Yasukawa K. Ihle J.N. Kishimoto T. Taga T. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 2285-2289Crossref PubMed Scopus (255) Google Scholar). Thus, a number of studies have shown that serine phosphorylation, in particular phosphorylation of Ser-727, can enhance the ability of STATs to promote transcriptional activity (25Ng J. Cantrell D. J. Biol. Chem. 1997; 272: 24542-24549Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 26Schuringa J. Jonk L.J.C. Dokter W.H.A. Vellenga E. Kruijer W. Biochem. J. 2000; 347: 89-96Crossref PubMed Scopus (90) Google Scholar). In the present study, we examine the mechanism by which heparin acts synergistically with IL-11 to induce both STAT3 activation and in vitro osteoclast formation. By using various serine kinase inhibitors we demonstrate that heparin enhances IL-11-induced STAT3 activation and thus, osteoclast formation, by a mechanism that is independent of STAT3 Ser-727 phosphorylation but involves up-regulation of the MAPK pathway. When taken together, these findings suggest a plausible mechanism by which heparin may cause bone loss when administered long-term. Materials—Thirty-day-old Swiss Webster and 15- to 17-day-old pregnant female C57 Bl/6 mice were obtained from Charles River IL-11 was from were obtained from All were from heparin and the serine kinase inhibitors PD098059, and were from were from as previously C. Deschamps P. D. Shaughnessy S.G. 2000; PubMed Scopus Google Scholar). were from to mice and into to were from the of bone by with at a of were by at a of in α-minimal essential fetal bovine and for and were in at a of 1 and for in FBS, and were with various serine kinase inhibitors for with either heparin IL-11 or both for were with using a cell by and in a and were by and in and Following the were and a protein was used to the protein of the to by electrophoretic mobility shift on the serum inducible of the was at the with using were with 3 of at for of in and a at were on a on and using a and a which is to bind and were in at a of 1 and for in FBS, and were for 1 with various serine kinase inhibitors or the inhibitor, with either heparin IL-11 or a of both heparin and IL-11, for was using an on a and a to at was using a to the of gp130 was used as a were on at for were in a and with a as a for were to in FBS, and at with increasing of heparin for in a series of were with heparin at a of and at for increasing of Following at were with and with and in and cell were on to a and with at were with for 3 with and with an Following the were and with was by the as were to in FBS, and for with either or were with either heparin IL-11 or IL-11 heparin and a the were and with and in and of the cell were at with 2 of and with protein for 1 to the were with and to to a were with at and with for 3 with a and by an were in at a of 1 and for in FBS, and were with for 1 with either heparin IL-11 or a of the for was using an and from of using and of and was with an using specific for and at for and and were at for 1 for were as the the respective were into at a cell of 2 the were with either 2 or for using Following of the the were to in for used in an in vitro osteoclast formation as In bone for the from Swiss Webster mice were and the was with using a with a C. Deschamps P. D. Shaughnessy S.G. 2000; PubMed Scopus Google Scholar). Once the were by and with at a of in In the were also with the serine kinase and either heparin IL-11 or a of heparin and IL-11. were with a and for tartrate-resistant acid activity Following the were and and the number of multinucleated was at C. Deschamps P. D. Shaughnessy S.G. 2000; PubMed Scopus Google Scholar). were in of was used to the results between the and a between and was an was at were using a for multiple of on the of Heparin to IL-11-induced STAT3 previously demonstrated that heparin enhances both IL-11-induced STAT3·DNA complex formation and the tyrosine phosphorylation status of STAT3 (13Walton K.J. Duncan J.M. Deschamps P. Shaughnessy S.G. Blood. 2002; 100: 2530-2536Crossref PubMed Scopus (39) Google Scholar). To the mechanism by which this we with various serine kinase inhibitors and by of an EMSA, the ability of heparin to promote STAT3·DNA complex formation in the presence or absence of IL-11. shown in nuclear from were able to form STAT3·DNA when with In contrast, no STAT3·DNA were when the nuclear were from Heparin was however, to enhance IL-11-induced STAT3·DNA complex formation when the nuclear from and were with that had with IL-11 alone of the with the phosphatidylinositol 3-kinase inhibitor, or the p38 MAPK inhibitor, had no effect on the ability of heparin to promote IL-11-induced STAT3·DNA complex formation. However, the inhibitor, PD098059, was found to completely the synergy between heparin and IL-11 In addition, the inhibitor, the ability of heparin to promote IL-11-induced STAT3·DNA complex formation, did complex formation in the presence of IL-11 alone results suggest that the ability of heparin to synergistically enhance STAT3·DNA binding is the ability of heparin to the MAPK pathway. of on the of Heparin to IL-11-induced gp130 the inhibitor, PD098059, was able to the ability of heparin to promote IL-11-induced STAT3·DNA we examined also heparin from the transcription of gp130, a that a within its promoter C.A. Manolagas S.C. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). in gp130 was by IL-11, heparin alone had no However, when with the ability of IL-11 to induce gp130 was that in its of the with the inhibitor, PD098059, no effect on IL-11-induced gp130 completely abolished the ability of heparin to act synergistically with IL-11 In contrast, the serine kinase phosphatidylinositol 3-kinase and p38 did effect IL-11-induced gp130 either in the presence or absence of heparin However, to its effect on STAT3·DNA complex formation, the inhibitor, IL-11-induced gp130 the ability of heparin to act synergistically with IL-11. of Heparin and on IL-11-induced STAT3 tyrosine phosphorylation is a prerequisite of STAT3 activation, serine phosphorylation of at Ser-727, is known to enhance STAT3 transcriptional activity (25Ng J. Cantrell D. J. Biol. Chem. 1997; 272: 24542-24549Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 26Schuringa J. Jonk L.J.C. Dokter W.H.A. Vellenga E. Kruijer W. Biochem. J. 2000; 347: 89-96Crossref PubMed Scopus (90) Google Scholar). with either the inhibitor, PD098059, or the inhibitor, the for with IL-11, or a of the were and the were with an for Ser-727 phosphorylation using an in of with IL-11 in a increase in serine phosphorylation However, heparin alone had no effect on Ser-727 phosphorylation nor did it enhance Ser-727 phosphorylation in the presence of IL-11. In addition, of the with either or did IL-11-induced Ser-727 phosphorylation, either in the presence or absence of When taken these results suggest that the ability of heparin to enhance STAT3 activation is independent of STAT3 Ser-727 of Heparin on and the inhibitor, PD098059, abolished the ability of heparin to promote both IL-11-induced STAT3·DNA complex formation and gp130 we to heparin was of and shown in heparin and activation in both a and of was obtained when the were for with heparin and was for at 2 to findings demonstrate that heparin can both and of Heparin and on IL-11-induced the of is a prerequisite of osteoclast we used to examine the ability of both heparin and to IL-11-induced shown in IL-11 by heparin alone had no However, when heparin was with IL-11, the of was that with IL-11 In contrast, when the were with PD098059, heparin was to act synergistically with IL-11 and induce When taken together, these findings suggest that heparin IL-11-induced in an of on the ability of heparin to enhance IL-11-induced of when with the of in when with the of in when with the of in heparin when with the of in when with the of in when with the of in in a of Heparin and on IL-11-induced in and activation by heparin was for the ability of heparin to promote IL-11-induced osteoclast formation, we of and bone with IL-11 in the presence or absence of heparin and the inhibitor, the were for and the number of multinucleated was shown in the formation of was when of and bone were with IL-11. with heparin alone had no However, when were with both heparin and IL-11, the ability of IL-11 to stimulate formation was In contrast, heparin was to promote IL-11-induced formation when the were in the presence of or when the were with When taken together, these results suggest that the ability of heparin to synergistically enhance IL-11-induced osteoclast formation is 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 (13Walton K.J. Duncan J.M. Deschamps P. Shaughnessy S.G. Blood. 2002; 100: 2530-2536Crossref PubMed Scopus (39) Google Scholar). In the study, we examine the mechanism by which this synergy Thus, by using various serine kinase inhibitors we demonstrate that the inhibitor, PD098059, the ability of heparin to enhance both IL-11-induced STAT3 activation and in vitro osteoclast formation. In addition, we demonstrate that heparin can increase Erk1/2 activation but that its effect on IL-11-induced STAT3 activation is independent of STAT3 Ser-727 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 which involves up-regulation of the MAPK pathway. In a study, we demonstrated that heparin enhances both IL-11-induced STAT3·DNA complex formation and either STAT3 tyrosine or serine phosphorylation (13Walton K.J. Duncan J.M. Deschamps P. Shaughnessy S.G. Blood. 2002; 100: 2530-2536Crossref PubMed Scopus (39) Google Scholar). In the study, we these findings and present to the that heparin enhances IL-11-induced STAT3 activation by the MAPK pathway. Thus, we demonstrate that heparin is able to increase and activation in both a time- and dose-dependent In addition, we that the inhibitor, PD098059, the ability of heparin to enhance IL-11-induced STAT3 activation and as a IL-11-induced gp130 1 and heparin is the MAPK or is However, heparin has shown to increase the binding of a cytokines of which the MAPK binding to their heparin has shown to enhance receptor binding and to in fetal M. G. Endocrinology. 1992; PubMed Scopus Google Scholar). In addition, heparin has shown to with a of and 2002; PubMed Scopus Google Scholar, A. C. H. 2002; Google Scholar, R. G. S. V. R. Proc. Acad. Sci. U. S. A. 2003; 100: PubMed Scopus Google Scholar, G. M. 1997; Scholar). STAT3·DNA binding and can be in a number of to bind DNA, STAT3 through a that phosphorylation of (22Zhong Z. Wen Z. Darnell Jr., J. Science. 1994; 264: 95-98Crossref PubMed Scopus (1735) Google Scholar, 23Lütticken C. Wegenka U.M. Yuan J. Buschmann J. Schindler C. Ziemiecki A. Harpur A.G. Wilks A.F. Yasukawa K. Taga T. Kishimoto T. Barbieri G. Pellegrini S. Sendtner M. Heinrich P.C. Horn F. Science. 1994; 263: 89-92Crossref PubMed Scopus (713) Google Scholar, 24Narazaki M. Witthuhn B.A. Yoshida K. Silvennoinen O. Yasukawa K. Ihle J.N. Kishimoto T. Taga T. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 2285-2289Crossref PubMed Scopus (255) Google Scholar). In addition, the transcriptional activity of STAT3 can be by phosphorylation at Ser-727 (25Ng J. Cantrell D. J. Biol. Chem. 1997; 272: 24542-24549Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 26Schuringa J. Jonk L.J.C. Dokter W.H.A. Vellenga E. Kruijer W. Biochem. J. 2000; 347: 89-96Crossref PubMed Scopus (90) Google Scholar). up-regulation of the MAPK by heparin to IL-11-induced STAT3·DNA complex formation and is studies in our have shown that heparin either STAT3 or Ser-727 phosphorylation, either in the absence or presence of IL-11. Furthermore, in the study, we demonstrate that the PD098059, of the synergy between heparin and IL-11, has no effect on STAT3 Ser-727 however, that heparin is STAT3 phosphorylation at a serine Ser-727 and that this results in an of STAT3·DNA complex formation and is to suggest that the phosphorylation of STAT3 on serine residues Ser-727 the transcriptional activity of STAT3 J. H. Schindler C. S. Science. 1995; PubMed Scopus Google Scholar, Z. Z. Darnell Jr., Cell. 1995; Full Text PDF PubMed Scopus Google Scholar, J. E. T.C. J. Cell. 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PubMed Scopus Google that activation of the in causes an increase in IL-11-induced STAT3 Ser-727 However, we found that the ability of to enhance STAT3 activation of STAT3 Ser-727 phosphorylation is to serine residues on STAT3 transcription which act with is we demonstrated that the ability of IL-11 to induce osteoclast formation was in the presence of heparin heparin alone had no effect (13Walton K.J. Duncan J.M. Deschamps P. Shaughnessy S.G. Blood. 2002; 100: 2530-2536Crossref PubMed Scopus (39) Google Scholar). In addition, we that heparin was able to enhance IL-11-induced osteoclast formation, it synergistically with IL-11 to induce the of receptor activator of nuclear factor-κB on the osteoblast cell in the presence of factor, has shown to be a prerequisite of osteoclast formation both in vitro and in vivo R. J. Biol. 1999; PubMed Scopus Google Scholar, H. N. N. K. M. S. A. K. M. A. E. T. K. Udagawa N. N. Suda T. Proc. Natl. Acad. Sci. U. S. 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In we have demonstrated that heparin enhances IL-11-induced STAT3 activation by a mechanism that is independent of STAT3 Ser-727 phosphorylation but involves up-regulation of the MAPK pathway. This a plausible mechanism by which heparin may with IL-11 to increase osteoclast formation and to heparin causes bone loss when administered long

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