Serum levels of sclerostin in cardiometabolic disorders during pregnancy

Serum levels of sclerostin in cardiometabolic disorders during pregnancy

Cytokine xxx (2015) xxx–xxx Contents lists available at ScienceDirect Cytokine journal homepage: www.journals.elsevier.com/cytokine Letter Serum l...

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Cytokine xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Cytokine journal homepage: www.journals.elsevier.com/cytokine

Letter

Serum levels of sclerostin in cardiometabolic disorders during pregnancy Martin Platz a,b, Holger Stepan c, Susanne Schrey c, Susan Kralisch a,b, Ulrike Wurst a,b, Ulrike Lossner a,b, Beate Jessnitzer a, Jürgen Kratzsch d, Michael Stumvoll a, Mathias Fasshauer a,b,1, Thomas Ebert a,b,⇑,1 a

University of Leipzig, Department of Endocrinology and Nephrology, 04103 Leipzig, Germany Leipzig University Medical Center, IFB AdiposityDiseases, 04103 Leipzig, Germany c University of Leipzig, Department of Obstetrics, 04103 Leipzig, Germany d University of Leipzig, Institute of Laboratory Medicine, 04103 Leipzig, Germany b

a r t i c l e

i n f o

Article history: Received 27 December 2014 Received in revised form 7 February 2015 Accepted 11 February 2015 Available online xxxx Keywords: Gestational diabetes mellitus Osteocyte Preeclampsia Pregnancy Sclerostin

a b s t r a c t Objective: Sclerostin has recently been introduced as a novel osteocyte-secreted factor which is associated with an adverse metabolic profile. However, regulation of circulating sclerostin in cardiometabolic disorders during pregnancy including gestational diabetes mellitus (GDM) and preeclampsia (PE) has not been comprehensively assessed, so far. Methods: Serum levels of sclerostin were quantified in 72 women with GDM and in 72 healthy, pregnant, gestational age-matched controls (study population 1). Furthermore, circulating sclerostin was assessed in 51 women with PE as compared to 51 pregnant controls in a second cohort (study population 2). Results: In the first study population (GDM), median [interquartile range] sclerostin levels were not significantly different in women with GDM as compared to controls (GDM: 19.2 [8.1] pmol/l; controls: 18.6 [7.1] pmol/l; p = 0.906). Interestingly, C reactive protein was a negative and independent predictor of circulating sclerostin in the GDM cohort in multivariate analysis. In study population 2 (PE), serum levels of sclerostin were not different between women with PE and controls (PE: 18.8 [9.2] pmol/l; controls: 19.3 [8.8] pmol/l; p = 0.504). Furthermore, the osteocyte-secreted factor was not related to any metabolic and gestational parameter in this cohort. Conclusions: Sclerostin serum levels are not associated with an adverse metabolic profile during pregnancy in women with GDM and PE. The physiological significance of different associations of circulating sclerostin between pregnancy and non-pregnant status needs to be determined in future experiments. Ó 2015 Elsevier Ltd. All rights reserved.

1. Introduction Gestational diabetes mellitus (GDM) and preeclampsia (PE) are cardiometabolic disorders during pregnancy leading to severe acute and chronic complications in both mother and newborn [1,2]. In the past few years, several cytokines have been suggested to be involved in the pathogenesis of cardiometabolic disorders during pregnancy including GDM and PE [3]. Recently, osteocyte-secreted cytokines have been introduced in metabolic disease states. Thus, sclerostin is an antagonist of the canonical Wnt signaling pathway binding Lrp5/6 with high affinity [4]. Interestingly, this novel osteocytesecreted factor is positively associated with facets of the metabolic syndrome including diabetes mellitus type 2 [5], obesity [6], and dyslipidemia [6], as well as atherosclerotic disease status [7]. ⇑ Corresponding author at: Liebigstr. 20, 04103 Leipzig, Germany. Tel.: +49 341 9713318; fax: +49 341 9713389. E-mail address: [email protected] (T. Ebert). 1 These authors equally contributed to this work.

Since sclerostin has not been comprehensively investigated in cardiometabolic disease states during pregnancy so far, we have quantified circulating sclerostin in women with GDM (study population 1) and PE (study population 2). 2. Research design and methods 2.1. Subjects 2.1.1. Study population 1 – sclerostin in women with GDM For the first part of the study, 72 women with GDM and 72 control women were recruited from the outpatient care unit of the Department of Endocrinology and Nephrology, University of Leipzig between 2006 and 2011. Study design of the GDM study, i.e. study population 1, has recently been described [8,9]. 2.1.2. Study population 2 – sclerostin in women with PE For the second part of the study, 51 women with PE and 51 control women were recruited from the Department of Obstetrics,

http://dx.doi.org/10.1016/j.cyto.2015.02.017 1043-4666/Ó 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Platz M et al. Serum levels of sclerostin in cardiometabolic disorders during pregnancy. Cytokine (2015), http:// dx.doi.org/10.1016/j.cyto.2015.02.017

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M. Platz et al. / Cytokine xxx (2015) xxx–xxx

Table 1 Baseline characteristics of the study population 1 (women with GDM) and 2 (women with PE). BMI, body mass-index before pregnancy; CRP, high sensitivity C reactive protein; DBP, diastolic blood pressure; FFA, free fatty acids; FG, fasting glucose; FI, fasting insulin; GDM, gestational diabetes mellitus; HbA1c, glycosylated hemoglobin A1c; HDL, highdensity lipoprotein; HOMA-IR, homeostasis model assessment of insulin resistance; LDL, low-density lipoprotein; PE, preeclampsia; SBP, systolic blood pressure; TG, triglycerides. Values for median (interquartile range) are shown. Study population 1

N Sclerostin (pmol/l) Age (years) Gestational age at blood sampling (days) Gestational age at delivery (days) Birth weight (g) BMI (kg/m2) SBP (mmHg) DBP (mmHg) HbA1c (%) HbA1c (mmol/mol) FG (mmol/l) Glucose 1 h (mmol/l) Glucose 2 h (mmol/l) FI (pmol/l) HOMA-IR Cholesterol (mmol/l) HDL cholesterol (mmol/l) LDL cholesterol (mmol/l) TG (mmol/l) FFA (mmol/l) Creatinine (lmol/l) CRP (mg/l) Leptin (lg/l) Adiponectin (mg/l) a

Study population 2

Controls

GDM

Controls

PE

72 18.6 (7.1) 29.0 (4.6) 199 (40) 276 (14) 3400 (768) 22.5 (6.9) 125 (16) 75 (13) 5.4 (0.6) 35.5 (6.6) 4.3 (0.5) 7.5 (1.6) 6.4 (1.8) 56.5 (37.3) 1.56 (0.98) 6.32 (1.87) 1.93 (0.54) 3.75 (1.58) 2.02 (1.41) 0.47 (0.31) 49.0 (11.0) 4.20 (4.63) 23.1 (11.8) 7.0 (3.9)

72 19.2 (8.1) 31.3 (7.7) 202 (33) 273 (14) 3400 (790) 24.5 (6.7) 120 (19) 73 (15) 5.4 (0.6) 35.5 (6.6) 4.5 (0.9)a 10.2 (1.8)a 8.7 (2.3)a 70.6 (65.7)a 2.06 (1.93)a 6.62 (1.77) 1.81 (0.80) 4.05 (1.92) 2.16 (1.32) 0.55 (0.32) 46.0 (9.8)a 3.99 (5.76) 26.5 (21.0) 6.7 (4.5)

51 19.3 (8.8) 30.0 (7.0) 197 (26) 274 (31) 3115 (1216) 22.0 (4.3) 115 (19) 70 (15) 3.6 (0.9) 58.9 (38.3) 1.33 (1.03) 6.48 (1.72) 1.75 (0.66) 3.89 (1.31) 2.20 (1.10) 0.43 (0.33) 54.0 (10.0) 2.46 (3.83) 20.4 (11.8) 7.4 (4.0)

51 18.8 (9.2) 30.0 (11.0) 208 (37)a 216 (38)a 1215 (904)a 22.7 (5.9) 159 (28)a 100 (18)a 3.8 (1.4)a 73.9 (64.4) 1.71 (2.13)a 6.66 (1.79) 1.83 (0.64) 3.41 (1.25)a 3.36 (1.17)a 0.79 (0.49)a 66.0 (16.0)a 8.17 (14.81)a 41.0 (36.9)a 11.7 (10.0)a

indicates p < 0.05 as assessed by Mann–Whitney-U-test in the respective study population.

University of Leipzig. Study design of the PE study, i.e. study population 2, has been described [10]. Both studies were approved by the local Ethics Committee and all subjects gave written informed consent before taking part in the study. 2.2. Assays In both studies, fasting serum samples were obtained and concentrations of sclerostin (Biomedica Medizinprodukte, Wien, Austria; distributed by Immunodiagnostik, Bensheim, Germany), as well as leptin and adiponectin (Mediagnost, Reutlingen, Germany) were quantified with ELISAs according to the manufacturers’ instructions. All other parameters were quantified by standard laboratory methods in a certified laboratory. 2.3. Statistical analysis SPSS software version 20.0 (IBM, Armonk, NY) was used in all statistical analyses. A p-value of <0.05 was considered as statistically significant in all analyses.

3. Results 3.1. Study population 1 – sclerostin in GDM Median serum sclerostin levels were not significantly different between women with GDM (19.2 [8.1] pmol/l) as compared to healthy and pregnant control women (18.6 [7.1] pmol/l) (p = 0.906) (Table 1). Multiple linear regression analysis revealed that CRP was a negative predictor of sclerostin levels independent of age, SBP, as well as FI (b = 0.184, p = 0.028).

3.2. Study population 2 – sclerostin in PE Median serum sclerostin levels were not significantly different between women with PE (18.8 [9.2] pmol/l) as compared to healthy and pregnant control women (19.3 [8.8] pmol/l) (p = 0.504) (Table 1). Interestingly, when analyzing all women, sclerostin was not independently correlated with any of the metabolic and pregnancy outcome parameters investigated in our study (data not shown).

4. Discussion To the best of our knowledge, this is the first report determining sclerostin levels in different cardiometabolic disease states during pregnancy. We show that serum sclerostin is not dysregulated in GDM and PE. Interestingly, Wild and co-workers elegantly demonstrate that sclerostin is not related to markers of bone turnover and not related to PE status in a small study comprising of 16 women with PE as compared to 16 healthy pregnant controls supporting our findings [11]. Most importantly, sclerostin is not correlated to any facet of the metabolic syndrome in both pregnant cohorts, in contrast to several non-pregnant human cohorts [5–7]. Our findings suggest that sclerostin does not play a significant role in the pathophysiology of GDM and PE. We demonstrate that CRP is a negative predictor of sclerostin in GDM. This is in accordance with a paper by Saad and co-workers in patients with ankylosing spondylitis during anti-tumor necrosis factor therapy [12]. However, we cannot detect any significant association of sclerostin with markers of inflammation in our PE study suggesting no crucial influence of this osteocytokine on inflammation during pregnancy. Clearly, the inflammatory capability of sclerostin during pregnancy has to be investigated in further studies.

Please cite this article in press as: Platz M et al. Serum levels of sclerostin in cardiometabolic disorders during pregnancy. Cytokine (2015), http:// dx.doi.org/10.1016/j.cyto.2015.02.017

M. Platz et al. / Cytokine xxx (2015) xxx–xxx

In conclusion, circulating sclerostin is not associated with an adverse metabolic profile during pregnancy in women with GDM and PE in contrast to studies in non-pregnant humans. Acknowledgements This study was supported by grants to M.F. from the Deutsche Forschungsgemeinschaft (DFG, SFB 1052/1, C06), the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1001 (IFB AdiposityDiseases, projects K7-58), and the Deutsche Hochdruckliga e.V.. Furthermore, T.E. was supported by the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1001 (IFB AdiposityDiseases, MetaRot program) and by MSD Sharp & Dohme GmbH (MSD Stipendium 2013 Diabetologie). Moreover, S.K. and T.E. were supported by the German Diabetes Association (DDG). In addition, M.P. was supported by the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1001 (IFB AdiposityDiseases, MD Pro1 program). References [1] Reece EA, Leguizamón G, Wiznitzer A. Gestational diabetes: the need for a common ground. The Lancet 2009;373:1789–97. [2] Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. The Lancet 2010;376:631–44.

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[3] Miehle K, Stepan H, Fasshauer M. Leptin, adiponectin and other adipokines in gestational diabetes mellitus and pre-eclampsia. Clin Endocrinol 2012;76: 2–11. [4] Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 2005;280:19883–7. [5] García-Martín A, Rozas-Moreno P, Reyes-García R, Morales-Santana S, GarcíaFontana B, García-Salcedo JA, et al. Circulating levels of sclerostin are increased in patients with type 2 diabetes mellitus. JCEM 2011;97:234–41. [6] Urano T, Shiraki M, Ouchi Y, Inoue S. Association of circulating sclerostin levels with fat mass and metabolic disease—related markers in Japanese postmenopausal women. JCEM 2012;97:E1473–7. [7] Morales-Santana S, García-Fontana B, García-Martín A, Rozas-Moreno P, García-Salcedo JA, Reyes-García R, et al. Atherosclerotic disease in type 2 diabetes is associated with an increase in sclerostin levels. Diabetes Care 2013;36:1667–74. [8] Ebert T, Stepan H, Schrey S, Kralisch S, Hindricks J, Hopf L, et al. Serum levels of irisin in gestational diabetes mellitus during pregnancy and after delivery. Cytokine 2014;65:153–8. [9] Ebert T, Hindricks J, Kralisch S, Lossner U, Jessnitzer B, Richter J, et al. Serum levels of fractalkine are associated with markers of insulin resistance in gestational diabetes. Diabet Med 2014;31:1014–7. [10] Stepan H, Kley K, Hindricks J, Kralisch S, Jank A, Schaarschmidt W, et al. Serum levels of the adipokine fibroblast growth factor-21 are increased in preeclampsia. Cytokine 2013;62:322–6. [11] Wild J, Pateisky P, Küssel L, Huf W, Ott J, Haslinger P, et al. Preeclampsia – a risk factor for osteoporosis? Analysis of maternal sclerostin levels and markers of bone turnover in patients with pre-eclampsia. Hypertens Pregnancy 2014;33:333–40. [12] Saad CG, Ribeiro AC, Moraes JC, Takayama L, Goncalves CR, Rodrigues MB, et al. Low sclerostin levels: a predictive marker of persistent inflammation in ankylosing spondylitis during anti-tumor necrosis factor therapy? Arthritis Res Ther 2012;14:R216.

Please cite this article in press as: Platz M et al. Serum levels of sclerostin in cardiometabolic disorders during pregnancy. Cytokine (2015), http:// dx.doi.org/10.1016/j.cyto.2015.02.017