High Serum Fractalkine is Associated with Lower Trabecular Bone Score in Premenopausal Women with Graves’ Disease

Abstract

Chemokine CX3CL1 (fractalkine) may be an important factor linking thyroid status and bone remodeling, through tetrac, a derivative of thyroxine. This study explores the relationship between serum fractalkine levels and parameters of thyroid status and bone in premenopausal women with Graves’ disease (GD) in comparison to healthy controls. This cross-sectional study included three premenopausal female groups: active GD; cured GD, and healthy age-, gender-, and BMI-matched controls. Measurement of serum fractalkine levels (Quantikine^® ELISA), total amino-terminal peptide of procollagen type 1 (P1NP), CTx, thyroid hormones, BMD and trabecular bone score (TBS) were performed in all study subjects. Sixty women (21, 16, and 23 in active GD, cured GD, and healthy control groups, respectively) were included. Serum fractalkine levels were higher (p<0.05) in active and cured GD subjects compared to healthy controls (mean 0.7±0.14; 0.93±0.15, and 0.48±0.13 ng/ml, respectively). Lumbar spine BMD was lowest in the cured GD group in comparison to active GD and control group subjects (0.926±0.03; 1.016±0.03; 1.051±0.03 g/cm²; p<0.05, respectively). TBS was lower (p<0.05) in both GD groups than controls being lowest in those with active GD (1.395±0.02; 1.402±0.02, 1.469±0.02, respectively). Serum fractalkine concentration was positively correlated with fT4, and negatively correlated with TBS values. GD in pre-menopausal females is associated with increased serum fractalkine concentration and decreased TBS. Fractalkine may be a currently unappreciated link between hyperthyroidism and bone; further research into this possibility is needed.

Key words

hyperthyroidism - trabecular bone score - fractalkine - bone turnover

• References

• 1 Williams GR, Bassett JH. Deiodinases: The balance of thyroid hormone: Local control of thyroid hormone action: Role of type 2 deiodinase. J Endocrinol 2011; 209: 261-272
• 2 Nicholls JJ, Brassill MJ, Williams GR, Bassett JH. The skeletal consequences of thyrotoxicosis. J Endocrinol 2012; 213: 209-221
• 3 Murphy E, Gluer CC, Reid DM, Felsenberg D, Roux C, Eastell R, Williams GR. Thyroid function within the upper normal range is associated with reduced bone mineral density and an increased risk of nonvertebral fractures in healthy euthyroid postmenopausal women. J Clin Endocrinol Metab 2010; 95: 3173-3181
• 4 Allelein S, Ehlers M, Goretzki S, Hermsen D, Feldkamp J, Haase M, Dringenberg T, Schmid C, Hautzel H, Schott M. Clinical evaluation of the first automated assay for the detection of stimulating TSH receptor autoantibodies. Horm Metab Res 2016; 48: 795-801
• 5 Abe E, Marians RC, Yu W, Wu XB, Ando T, Li Y, Iqbal J, Eldeiry L, Rajendren G, Blair HC, Davies TF, Zaidi M. TSH is a negative regulator of skeletal remodeling. Cell 2003; 115: 151-162
• 6 Galliford TM, Murphy E, Williams AJ, Bassett JH, Williams GR. Effects of thyroid status on bone metabolism: A primary role for thyroid stimulating hormone or thyroid hormone?. Minerva Endocrinol 2005; 30: 237-246
• 7 Sampath TK, Simic P, Sendak R, Draca N, Bowe AE, O'Brien S, Schiavi SC, McPherson JM, Vukicevic S. Thyroid-stimulating hormone restores bone volume, microarchitecture, and strength in aged ovariectomized rats. J Bone Miner Res 2007; 22: 849-859
• 8 Kim DJ, Khang YH, Koh JM, Shong YK, Kim GS. Low normal TSH levels are associated with low bone mineral density in healthy postmenopausal women. Clin Endocrinol (Oxf) 2006; 64: 86-90
• 9 Morris MS. The association between serum thyroid-stimulating hormone in its reference range and bone status in postmenopausal American women. Bone 2007; 40: 1128-1134
• 10 van Rijn LE, Pop VJ, Williams GR. Low bone mineral density is related to high physiological levels of free thyroxine in peri-menopausal women. Eur J Endocrinol 2014; 170: 461-468
• 11 Raggatt LJ, Partridge NC. Cellular and molecular mechanisms of bone remodeling. J Biol Chem 2010; 285: 25103-25108
• 12 Makowka A, Glyda M, Majewska ER, Nowicki M. Varying patterns of biomarkers of mineral and bone metabolism after kidney transplantation. Horm 2017; 49: 618-624
• 13 Nanki T, Imai T, Kawai S. Fractalkine/CX3CL1 in rheumatoid arthritis. Mod Rheumatol 2017; 27: 392-397
• 14 Edsfeldt A, Grufman H, Asciutto G, Nitulescu M, Persson A, Nilsson MMN, Nilsson J, Goncalves I. Circulating cytokines reflect the expression of pro-inflammatory cytokines in atherosclerotic plaques. Atherosclerosis 2015; 241: 443-449
• 15 Pathak JL, Bakker AD, Verschueren P, Lems WF, Luyten FP, Klein-Nulend J, Bravenboer N. CXCL8 and CCL20 enhance osteoclastogenesis via modulation of cytokine production by human primary osteoblasts. PLoS One 2015; 10: e0131041
• 16 Koizumi K, Saitoh Y, Minami T, Takeno N, Tsuneyama K, Miyahara T, Takashi N, Sakurai H, Takano Y, Nishimura M, Imai T, Yoshie O, Saiki I. Role of CX3CL1/fractalkine in osteoclast differentiation and bone resorption. J Immunol 2009; 183: 7825-7831
• 17 Davis PJ, Glinsky GV, Lin HY, Mousa SA. Actions of thyroid hormone analogues on chemokines. J Immunol Res 2016; 3147671
• 18 McClung MR. Inhibition of RANKL as a treatment for osteoporosis: Preclinical and early clinical studies. Curr Osteoporos Rep 2006; 4: 28-33
• 19 Smolen JS, Aletaha D, Keystone E. Superior efficacy of combination therapy for rheumatoid arthritis: Fact or fiction?. Arthritis Rheum 2005; 52: 2975-2983
• 20 Yoneda T, Hiraga T. Crosstalk between cancer cells and bone microenvironment in bone metastasis. Biochem Biophys Res Commun. 2005; 328: 679-687
• 21 Zhukouskaya VV, Eller-Vainicher C, Gaudio A, Privitera F, Cairoli E, Ulivieri FM, Palmieri S, Morelli V, Grancini V, Orsi E, Masserini B, Spada AM, Fiore CE, Chiodini I. The utility of lumbar spine trabecular bone score and femoral neck bone mineral density for identifying asymptomatic vertebral fractures in well-compensated type 2 diabetic patients. Osteoporos Int 2016; 27: 49-56
• 22 Leib ES, Winzenrieth R. Bone status in glucocorticoid-treated men and women. Osteoporos Int 2016; 27: 39-48
• 23 Eller-Vainicher C, Filopanti M, Palmieri S, Ulivieri FM, Morelli V, Zhukouskaya VV, Cairoli E, Pino R, Naccarato A, Verga U, Scillitani A, Beck-Peccoz P, Chiodini I. Bone quality, as measured by trabecular bone score, in patients with primary hyperparathyroidism. Eur J Endocrinol 2013; 169: 155-162
• 24 Breban S, Briot K, Kolta S, Paternotte S, Ghazi M, Fechtenbaum J, Roux C. Identification of rheumatoid arthritis patients with vertebral fractures using bone mineral density and trabecular bone score. J Clin Densitom 2012; 15: 260-266
• 25 Hwangbo Y, Kim JH, Kim SW, Park YJ, Park DJ, Kim SY, Shin CS, Cho NH. High-normal free thyroxine levels are associated with low trabecular bone scores in euthyroid postmenopausal women. Osteoporos Int 2016; 27: 457-462
• 26 Hunter DJ, Sambrook PN. Bone loss. Epidemiology of bone loss. Arthritis Res 2000; 2: 441-445