Download PDF
Thromb Haemost 2020; 120(07): 1108-1115
DOI: 10.1055/s-0040-1712448
Endothelium and Angiogenesis
Georg Thieme Verlag KG Stuttgart · New York

Differential Osteoprotegerin Kinetics after Stimulation with Desmopressin and Lipopolysaccharides In Vivo

Nina Buchtele
1   Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
2   Department of Medicine I, Medical University of Vienna, Vienna, Austria
,
Katarina D. Kovacevic
1   Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
,
Christine Brostjan 
3   Department of Surgery, Medical University of Vienna, Vienna, Austria
,
Michael Schwameis
4   Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria
,
Hubert Hayden
3   Department of Surgery, Medical University of Vienna, Vienna, Austria
,
Ulla Derhaschnig
1   Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
,
Christa Firbas
1   Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
,
Bernd Jilma
1   Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
,
Christian Schoergenhofer
1   Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
› Author Affiliations Funding This study was funded by the Austrian Science Fund FWF grant SFB54–04/APF05404FW.
Further Information

Publication History

24 February 2020

18 April 2020

Publication Date:
29 May 2020 (online)

Also available at
    Permissions and Reprints

Abstract

Osteoprotegerin (OPG) regulates bone metabolism by reducing the activation of osteoclasts, but may also be involved in blood vessel calcification and atherosclerosis. Within endothelial cells OPG is stored in Weibel–Palade bodies (WPBs). Blood kinetics of OPG are essentially unknown. We aimed to assess these using two distinct in vivo models; one after stimulation with desmopressin (DDAVP) and another after stimulation with lipopolysaccharide (LPS). Both clinical trials were conducted at the Department of Clinical Pharmacology at the Medical University of Vienna, Austria. Participants received desmopressin (0.3 µg/kg), LPS (2 ng/kg), or placebo (sodium chloride 0.9%) with subsequent blood sampling at time points up to 24 hours after administration. The primary objective of this study was to investigate the plasma kinetics of OPG after stimulation with desmopressin and LPS. Secondary analyses included the release of other WPB contents including von Willebrand factor (vWF). This analysis included 31 healthy volunteers (n = 16 for desmopressin and placebo, n = 15 for LPS). Infusion of desmopressin did not increase OPG concentrations compared with placebo, while LPS infusion significantly increased OPG levels, both compared with desmopressin (p < 0.0001) and to placebo (p = 0.004), with a maximum of ∼twofold increase in OPG levels ∼6 hours after infusion. von Willebrand factor levels increased after both desmopressin and LPS infusion (p < 0.0001), with a maximum of ∼threefold increase 2 hours after desmopressin and a maximum of ∼twofold increase 6 hours after LPS administration. In conclusion, we report that, in contrast to vWF, OPG is not released upon stimulation with desmopressin, but increases significantly during experimental endotoxemia.

Keywords

osteoprotegerin - Weibel–Palade bodies - secretion/exocytosis - endothelial cells

Authors' Contributions

Conceptualization: N.B., C.S., and B.J.; Data curation: N.B., U.D., C.F., and C.S.; Formal analysis: C.S., B.J., and M.S.; Funding acquisition: B.J.; Methodology: K.K., C.B., H.H., and M.S.; Project administration: N.B., C.S.; Supervision: B.J.; Writing – original draft: N.B. and C.S.; Writing – review and editing: K.K., C.B., M.S., H.H., U.D., C.F., and B.J.


Supplementary Material

 

  • References

  • 1 Rochette L, Meloux A, Rigal E, Zeller M, Cottin Y, Vergely C. The role of osteoprotegerin and its ligands in vascular function. Int J Mol Sci 2019; 20 (03) E705
    CrossrefPubMedSearch in Google Scholar
  • 2 Simonet WS, Lacey DL, Dunstan CR. , et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997; 89 (02) 309-319
    CrossrefPubMedSearch in Google Scholar
  • 3 Bucay N, Sarosi I, Dunstan CR. , et al. osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998; 12 (09) 1260-1268
    CrossrefPubMedSearch in Google Scholar
  • 4 Price PA, June HH, Buckley JR, Williamson MK. Osteoprotegerin inhibits artery calcification induced by warfarin and by vitamin D. Arterioscler Thromb Vasc Biol 2001; 21 (10) 1610-1616
    CrossrefPubMedSearch in Google Scholar
  • 5 Malyankar UM, Scatena M, Suchland KL, Yun TJ, Clark EA, Giachelli CM. Osteoprotegerin is an alpha vbeta 3-induced, NF-kappa B-dependent survival factor for endothelial cells. J Biol Chem 2000; 275 (28) 20959-20962
    CrossrefPubMedSearch in Google Scholar
  • 6 Bennett BJ, Scatena M, Kirk EA. , et al. Osteoprotegerin inactivation accelerates advanced atherosclerotic lesion progression and calcification in older ApoE-/- mice. Arterioscler Thromb Vasc Biol 2006; 26 (09) 2117-2124
    CrossrefPubMedSearch in Google Scholar
  • 7 Browner WS, Lui LY, Cummings SR. Associations of serum osteoprotegerin levels with diabetes, stroke, bone density, fractures, and mortality in elderly women. J Clin Endocrinol Metab 2001; 86 (02) 631-637
    PubMedSearch in Google Scholar
  • 8 Yilmaz MI, Siriopol D, Saglam M. , et al. Osteoprotegerin in chronic kidney disease: associations with vascular damage and cardiovascular events. Calcif Tissue Int 2016; 99 (02) 121-130
    CrossrefPubMedSearch in Google Scholar
  • 9 Siller-Matula J, Lang IM, Schoergenhofer C, Roest M, Jilma B. Interdependence between osteoprotegerin and active von Willebrand factor in long-term cardiovascular mortality prediction in patients undergoing percutaneous coronary intervention. Thromb Haemost 2017; 117 (09) 1730-1738
    Thieme ConnectPubMedSearch in Google Scholar
  • 10 Tousoulis D, Siasos G, Maniatis K. , et al. Serum osteoprotegerin and osteopontin levels are associated with arterial stiffness and the presence and severity of coronary artery disease. Int J Cardiol 2013; 167 (05) 1924-1928
    CrossrefPubMedSearch in Google Scholar
  • 11 Rochette L, Meloux A, Rigal E. , et al. The role of osteoprotegerin in vascular calcification and bone metabolism: the basis for developing new therapeutics. Calcif Tissue Int 2019; 105 (03) 239-251
    CrossrefPubMedSearch in Google Scholar
  • 12 Kostenuik PJ. Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength. Curr Opin Pharmacol 2005; 5 (06) 618-625
    CrossrefPubMedSearch in Google Scholar
  • 13 Bone HG, Wagman RB, Brandi ML. , et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol 2017; 5 (07) 513-523
    CrossrefPubMedSearch in Google Scholar
  • 14 Helas S, Goettsch C, Schoppet M. , et al. Inhibition of receptor activator of NF-kappaB ligand by denosumab attenuates vascular calcium deposition in mice. Am J Pathol 2009; 175 (02) 473-478
    CrossrefPubMedSearch in Google Scholar
  • 15 Samelson EJ, Miller PD, Christiansen C. , et al. RANKL inhibition with denosumab does not influence 3-year progression of aortic calcification or incidence of adverse cardiovascular events in postmenopausal women with osteoporosis and high cardiovascular risk. J Bone Miner Res 2014; 29 (02) 450-457
    CrossrefPubMedSearch in Google Scholar
  • 16 Zannettino AC, Holding CA, Diamond P. , et al. Osteoprotegerin (OPG) is localized to the Weibel-Palade bodies of human vascular endothelial cells and is physically associated with von Willebrand factor. J Cell Physiol 2005; 204 (02) 714-723
    CrossrefPubMedSearch in Google Scholar
  • 17 Rondaij MG, Bierings R, Kragt A, van Mourik JA, Voorberg J. Dynamics and plasticity of Weibel-Palade bodies in endothelial cells. Arterioscler Thromb Vasc Biol 2006; 26 (05) 1002-1007
    CrossrefPubMedSearch in Google Scholar
  • 18 Jilma B, Eichler HG, Vondrovec B. , et al. Effects of desmopressin on circulating P-selectin. Br J Haematol 1996; 93 (02) 432-436
    CrossrefPubMedSearch in Google Scholar
  • 19 Schoergenhofer C, Schwameis M, Gelbenegger G. , et al. Inhibition of protease-activated receptor (PAR1) reduces activation of the endothelium, coagulation, fibrinolysis and inflammation during human endotoxemia. Thromb Haemost 2018; 118 (07) 1176-1184
    Thieme ConnectPubMedSearch in Google Scholar
  • 20 Steinlechner B, Zeidler P, Base E. , et al. Patients with severe aortic valve stenosis and impaired platelet function benefit from preoperative desmopressin infusion. Ann Thorac Surg 2011; 91 (05) 1420-1426
    CrossrefPubMedSearch in Google Scholar
  • 21 Jilma-Stohlawetz P, Knöbl P, Gilbert JC, Jilma B. The anti-von Willebrand factor aptamer ARC1779 increases von Willebrand factor levels and platelet counts in patients with type 2B von Willebrand disease. Thromb Haemost 2012; 108 (02) 284-290
    Thieme ConnectPubMedSearch in Google Scholar
  • 22 Lethagen S, Frick K, Sterner G. Antidiuretic effect of desmopressin given in hemostatic dosages to healthy volunteers. Am J Hematol 1998; 57 (02) 153-159
    CrossrefPubMedSearch in Google Scholar
  • 23 Schillemans M, Karampini E, Kat M, Bierings R. Exocytosis of Weibel-Palade bodies: how to unpack a vascular emergency kit. J Thromb Haemost 2019; 17 (01) 6-18
    CrossrefPubMedSearch in Google Scholar
  • 24 Babich V, Meli A, Knipe L. , et al. Selective release of molecules from Weibel-Palade bodies during a lingering kiss. Blood 2008; 111 (11) 5282-5290
    CrossrefPubMedSearch in Google Scholar
  • 25 Kaufmann JE, Iezzi M, Vischer UM. Desmopressin (DDAVP) induces NO production in human endothelial cells via V2 receptor- and cAMP-mediated signaling. J Thromb Haemost 2003; 1 (04) 821-828
    CrossrefPubMedSearch in Google Scholar
  • 26 Kaufmann JE, Oksche A, Wollheim CB, Günther G, Rosenthal W, Vischer UM. Vasopressin-induced von Willebrand factor secretion from endothelial cells involves V2 receptors and cAMP. J Clin Invest 2000; 106 (01) 107-116
    CrossrefPubMedSearch in Google Scholar
  • 27 Carnevale R, Raparelli V, Nocella C. , et al. Gut-derived endotoxin stimulates factor VIII secretion from endothelial cells. Implications for hypercoagulability in cirrhosis. J Hepatol 2017; 67 (05) 950-956
    CrossrefPubMedSearch in Google Scholar
  • 28 Juul KV, Bichet DG, Nielsen S, Nørgaard JP. The physiological and pathophysiological functions of renal and extrarenal vasopressin V2 receptors. Am J Physiol Renal Physiol 2014; 306 (09) F931-F940
    CrossrefPubMedSearch in Google Scholar
  • 29 Kaufmann JE, Vischer UM. Cellular mechanisms of the hemostatic effects of desmopressin (DDAVP). J Thromb Haemost 2003; 1 (04) 682-689
    CrossrefPubMedSearch in Google Scholar
  • 30 Kobayashi-Sakamoto M, Hirose K, Isogai E, Chiba I. NF-kappaB-dependent induction of osteoprotegerin by Porphyromonas gingivalis in endothelial cells. Biochem Biophys Res Commun 2004; 315 (01) 107-112
    CrossrefPubMedSearch in Google Scholar
  • 31 Han X, Li P, Yang Z. , et al. Zyxin regulates endothelial von Willebrand factor secretion by reorganizing actin filaments around exocytic granules. Nat Commun 2017; 8: 14639
    CrossrefPubMedSearch in Google Scholar
  • 32 Romani de Wit T, Rondaij MG, Hordijk PL, Voorberg J, van Mourik JA. Real-time imaging of the dynamics and secretory behavior of Weibel-Palade bodies. Arterioscler Thromb Vasc Biol 2003; 23 (05) 755-761
    CrossrefPubMedSearch in Google Scholar
  • 33 Knipe L, Meli A, Hewlett L. , et al. A revised model for the secretion of tPA and cytokines from cultured endothelial cells. Blood 2010; 116 (12) 2183-2191
    PubMedSearch in Google Scholar
  • 34 Schoergenhofer C, Matzneller P, Mußbacher M. , et al. Colistin dampens fibrinolysis and endothelial activation during endotoxaemia. A randomised, double blind trial. Thromb Haemost 2017; 117 (09) 1714-1721
    Thieme ConnectPubMedSearch in Google Scholar
  • 35 DeLa Cadena RA, Majluf-Cruz A, Stadnicki A. , et al. Recombinant tumor necrosis factor receptor p75 fusion protein (TNFR:Fc) alters endotoxin-induced activation of the kinin, fibrinolytic, and coagulation systems in normal humans. Thromb Haemost 1998; 80 (01) 114-118
    Thieme ConnectPubMedSearch in Google Scholar
  • 36 Matzneller P, Strommer S, Drucker C. , et al. Colistin reduces LPS-triggered inflammation in a human sepsis model in vivo: a randomized controlled trial. Clin Pharmacol Ther 2017; 101 (06) 773-781
    PubMedSearch in Google Scholar
  • 37 Hasikova L, Pavlikova M, Hulejova H. , et al. Serum uric acid increases in patients with systemic autoimmune rheumatic diseases after 3 months of treatment with TNF inhibitors. Rheumatol Int 2019; 39 (10) 1749-1757
    CrossrefPubMedSearch in Google Scholar
  • 38 Zhang C, Shu W, Zhou G. , et al. Anti-TNF-α therapy suppresses proinflammatory activities of mucosal neutrophils in inflammatory bowel disease. Mediators Inflamm 2018; 2018: 3021863
    PubMedSearch in Google Scholar
  • 39 Vicente V, Estellés A, Laso J, Moraleda JM, Rivera J, Aznar J. Repeated infusions of DDAVP induce low response of FVIII and vWF but not of plasminogen activators. Thromb Res 1993; 70 (02) 117-122
    CrossrefPubMedSearch in Google Scholar
  • 40 Reiter RA, Mayr F, Blazicek H. , et al. Desmopressin antagonizes the in vitro platelet dysfunction induced by GPIIb/IIIa inhibitors and aspirin. Blood 2003; 102 (13) 4594-4599
    CrossrefPubMedSearch in Google Scholar
  • 41 Valentijn KM, Sadler JE, Valentijn JA, Voorberg J, Eikenboom J. Functional architecture of Weibel-Palade bodies. Blood 2011; 117 (19) 5033-5043
    CrossrefPubMedSearch in Google Scholar
  • 42 Huber D, Cramer EM, Kaufmann JE. , et al. Tissue-type plasminogen activator (t-PA) is stored in Weibel-Palade bodies in human endothelial cells both in vitro and in vivo. Blood 2002; 99 (10) 3637-3645
    CrossrefPubMedSearch in Google Scholar
  • 43 Chen J, Chung DW. Inflammation, von Willebrand factor, and ADAMTS13. Blood 2018; 132 (02) 141-147
    PubMedSearch in Google Scholar
  • 44 Paleolog EM, Crossman DC, McVey JH, Pearson JD. Differential regulation by cytokines of constitutive and stimulated secretion of von Willebrand factor from endothelial cells. Blood 1990; 75 (03) 688-695
    CrossrefPubMedSearch in Google Scholar
  • 45 Schorer AE, Moldow CF, Rick ME. Interleukin 1 or endotoxin increases the release of von Willebrand factor from human endothelial cells. Br J Haematol 1987; 67 (02) 193-197
    CrossrefPubMedSearch in Google Scholar
  • 46 Kemperman H, Schrijver IT, Roest M, Kesecioglu J, van Solinge WW, de Lange DW. Osteoprotegerin is higher in sepsis than in noninfectious SIRS and predicts 30-day mortality of SIRS patients in the intensive care. J Appl Lab Med 2019; 3 (04) 559-568
    PubMedSearch in Google Scholar
  • 47 Rex S, Beaulieu LM, Perlman DH. , et al. Immune versus thrombotic stimulation of platelets differentially regulates signalling pathways, intracellular protein-protein interactions, and alpha-granule release. Thromb Haemost 2009; 102 (01) 97-110
    Thieme ConnectPubMedSearch in Google Scholar
  • 48 Italiano Jr JE, Richardson JL, Patel-Hett S. , et al. Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood 2008; 111 (03) 1227-1233
    CrossrefPubMedSearch in Google Scholar
  • 49 Chollet ME, Brouland JP, Bal dit Sollier C, Bauduer F, Drouet L, Bellucci S. Evidence of a colocalisation of osteoprotegerin (OPG) with von Willebrand factor (VWF) in platelets and megakaryocytes alpha granules. Studies from normal and grey platelets. Br J Haematol 2010; 148 (05) 805-807
    CrossrefPubMedSearch in Google Scholar
  • 50 Vischer UM, Wollheim CB. Epinephrine induces von Willebrand factor release from cultured endothelial cells: involvement of cyclic AMP-dependent signalling in exocytosis. Thromb Haemost 1997; 77 (06) 1182-1188
    Thieme ConnectPubMedSearch in Google Scholar
  • 51 Vischer UM, Barth H, Wollheim CB. Regulated von Willebrand factor secretion is associated with agonist-specific patterns of cytoskeletal remodeling in cultured endothelial cells. Arterioscler Thromb Vasc Biol 2000; 20 (03) 883-891
    CrossrefPubMedSearch in Google Scholar
  • 52 Kanwar S, Woodman RC, Poon MC. , et al. Desmopressin induces endothelial P-selectin expression and leukocyte rolling in postcapillary venules. Blood 1995; 86 (07) 2760-2766
    CrossrefPubMedSearch in Google Scholar