Vol 88, No 4 (2017)
Research paper
Published online: 2017-04-28
Effects of 17β-estradioland raloxifene on endothelial OPG and RANKL secretion
Abstract
Objectives: This study aims to asses the effects of estradiol vs. raloxifene on the levels of osteoprotegerin and soluble Receptor Activator of Nuclear Factor kB Ligand (sRANKL) in Human Umbilical Vein Endothelial Cells (HUVEC) culture in standard and calcifying medium.
Material and methods: Human Umbilical Vein Endothelial Cells were isolated from human umbilical vein by standard method. The supernatant concentrations of osteoprotegerin (OPG) and sRANKL (ELISA) were determined after incubation with glicerophosphate, estradiol , raloxifene, glicerophoshate and estradiol, glicerophosphate and raloxifene in comparison with control group at four designated time points (0, 1, 2 and 4 days of incubation).
Results: Incubation of estradiol with HUVEC colony lowered the OPG level significantly after day 2 and 4. Meantime, the level of sRANKL was stable. Raloxifene added to standard growth medium also significantly lowered OPG concentration after day 4 only, with no impact on sRANKL concentration. When added to calcifying medium, both estradiol and raloxifene significantly changed OPG level during the experiment. In all treated groups OPG levels were lower than in groups exposed to calcifying medium only. Neither estradiol, nor raloxifene changed sRANKL levels during the experiment.
Conclusions: Estradiol and raloxifene affect OPG secretion from endothelial cells in vitro which may suggest their modifying role in pathogenesis of vascular calcification in postmenopausal women
Keywords: vascular calcificationOPGsRANKLmenopauseestrogensraloxifene
References
- Tanimura A, McGregor DH, Anderson HC. Matrix vesicles in atherosclerotic calcification. Proc Soc Exp Biol Med. 1983; 172(2): 173–177.
- Byon CH, Chen Y. Molecular Mechanisms of Vascular Calcification in Chronic Kidney Disease: The Link between Bone and the Vasculature. Curr Osteoporos Rep. 2015; 13(4): 206–215.
- Liu W, Zhang Y, Yu CM, et al. Current understanding of coronary artery calcification. J Geriatr Cardiol. 2015; 12(6): 668–675.
- Wu PC, Zheng CM, Liao MT, et al. Bone turnover and vascular calcification. J Nephrol Ther. 2014; 4: 171.
- Shargorodsky M, Boaz M, Luckish A, et al. Osteoprotegerin as an independent marker of subclinical atherosclerosis in osteoporotic postmenopausal women. Atherosclerosis. 2009; 204(2): 608–611.
- 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(2): 473–478.
- Karwowski W, Naumnik B, Szczepański M, et al. The mechanism of vascular calcification - a systematic review. Med Sci Monit. 2012; 18(1): RA1–R11.
- Mackey RH, Kuller LH, Sutton-Tyrrell K, et al. Hormone therapy, lipoprotein subclasses, and coronary calcification: the Healthy Women Study. Arch Intern Med. 2005; 165(5): 510–515.
- Manson JE, Allison MA, Carr JJ, et al. Women's Health Initiative and Women's Health Initiative-Coronary Artery Calcium Study Investigators, WHI and WHI-CACS Investigators. Estrogen therapy and coronary-artery calcification. N Engl J Med. 2007; 356(25): 2591–2602.
- Jeon GH, Kim SH, Yun SC, et al. Association between serum estradiol level and coronary artery calcification in postmenopausal women. Menopause. 2010; 17(5): 902–907.
- Doherty TM, Asotra K, Fitzpatrick LA, et al. Calcification in atherosclerosis: bone biology and chronic inflammation at the arterial crossroads. Proc Natl Acad Sci U S A. 2003; 100(20): 11201–11206.
- Takahashi K, Ohmichi M, Yoshida M, et al. Both estrogen and raloxifene cause G1 arrest of vascular smooth muscle cells. J Endocrinol. 2003; 178(2): 319–329.
- Oktem M, Atar I, Zeyneloglu HB, et al. Raloxifene has favourable effects on metabolic parameters but has no effect on left ventricular function in postmenopausal women. Pharmacol Res. 2008; 57(5): 364–368.
- Eilertsen AL, Sandvik L, Steinsvik B, et al. Differential impact of conventional-dose and low-dose postmenopausal hormone therapy, tibolone and raloxifene on C-reactive protein and other inflammatory markers. J Thromb Haemost. 2008; 6(6): 928–934.
- Choi BG, Vilahur G, Zafar MU, et al. Selective estrogen receptor modulation influences atherosclerotic plaque composition in a rabbit menopause model. Atherosclerosis. 2008; 201(1): 76–84.
- Nanetti L, Camilletti A, Francucci CM, et al. Role of raloxifene on platelet metabolism and plasma lipids. Eur J Clin Invest. 2008; 38(2): 117–125.
- Mosca L, Grady D, Barrett-Connor E, et al. Effect of raloxifene on stroke and venous thromboembolism according to subgroups in postmenopausal women at increased risk of coronary heart disease. Stroke. 2009; 40(1): 147–155.
- Chan YC, Leung FP, Wong WT, et al. Therapeutically relevant concentrations of raloxifene dilate pressurized rat resistance arteries via calcium-dependent endothelial nitric oxide synthase activation. Arterioscler Thromb Vasc Biol. 2010; 30(5): 992–999.
- Leung FP, Yung LM, Leung HS, et al. Therapeutic concentrations of raloxifene augment nitric oxide-dependent coronary artery dilatation in vitro. Br J Pharmacol. 2007; 152(2): 223–229.
- Choi BG, Vilahur G, Cardoso L, et al. Ovariectomy increases vascular calcification via the OPG/RANKL cytokine signalling pathway. Eur J Clin Invest. 2008; 38(4): 211–217.
- Fernández-García D, Muñoz-Torres M, Mezquita-Raya P, et al. Effects of raloxifene therapy on circulating osteoprotegerin and RANK ligand levels in post-menopausal osteoporosis. J Endocrinol Invest. 2008; 31(5): 416–421.
- Rzewuska-Lech E, Jayachandran M, Fitzpatrick LA, et al. Differential effects of 17beta-estradiol and raloxifene on VSMC phenotype and expression of osteoblast-associated proteins. Am J Physiol Endocrinol Metab. 2005; 289(1): E105–E112.
- Higgins CL, Isbilir S, Basto P, et al. Distribution of alkaline phosphatase, osteopontin, RANK ligand and osteoprotegerin in calcified human carotid atheroma. Protein J. 2015; 34(5): 315–328.
- Sasso GR, Florencio-Silva R, Simões RS, et al. Elevated serum osteoprotegerin levels in women: friend or foe? Rev Assoc Med Bras (1992). 2015; 61(6): 524–529.
- Ziegler S, Kudlacek S, Luger A, et al. Osteoprotegerin plasma concentrations correlate with severity of peripheral artery disease. Atherosclerosis. 2005; 182(1): 175–180.
- Ueland T, Yndestad A, Dahl CP, et al. TNF revisited: osteoprotegerin and TNF-related molecules in heart failure. Curr Heart Fail Rep. 2012; 9(2): 92–100.
- Aksu F, Ozçelik F, Kunduracilar H, et al. The relation between the levels of osteoprotegerin and the degree of coronary artery disease in patients with acute coronary syndrome and stable angina pectoris. Kardiol Pol. 2014; 72(1): 34–41.
- Montagnana M, Lippi G, Danese E, et al. The role of osteoprotegerin in cardiovascular disease. Ann Med. 2013; 45(3): 254–264.
- Bjerre M. Osteoprotegerin (OPG) as a biomarker for diabetic cardiovascular complications. Springerplus. 2013; 2: 658.
- Lieb W, Gona P, Larson MG, et al. Biomarkers of the osteoprotegerin pathway: clinical correlates, subclinical disease, incident cardiovascular disease, and mortality. Arterioscler Thromb Vasc Biol. 2010; 30(9): 1849–1854.
- Poornima IG, Mackey RH, Buhari AM, et al. Relationship between circulating serum osteoprotegerin and total receptor activator of nuclear κ-B ligand levels, triglycerides, and coronary calcification in postmenopausal women. Menopause. 2014; 21(7): 702–710.
- 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(2): 450–457.
- Andersen GØ, Knudsen EC, Aukrust P, et al. Elevated serum osteoprotegerin levels measured early after acute ST-elevation myocardial infarction predict final infarct size. Heart. 2011; 97(6): 460–465.
- Lekesiz K, Naumnik B, Borysewicz-Sanczyk H, et al. Effect of unfractionated heparin, enoxaparin and sulodexide on the relations between secretion and expression of OPG, RANKL and vWF in HUVEC. Folia Histochem Cytobiol. 2013; 51(2): 156–163.
