- Email: [email protected]
Inflammation and vascular calcification in chronic kidney disease: The role of Fetuin-A
Cytokine 45 (2009) 70–71
Contents lists available at ScienceDirect
Cytokine journal homepage: www.elsevier.com/locate/issn/10434666
Letter Inflammation and vascular calcification in chronic kidney disease: The role of Fetuin-A In this Issue of the Journal, we read with interest the article by Dervisoglu et al. [1] on the negative association between serum Fetuin-A levels and concentrations of the inflammatory cytokines IL-1b, IL-6, and TNFa in chronic kidney disease (CKD) and haemodialysis (HD) patients. The authors’ results support the hypothesis of inflammation-dependent down-regulation of Fetuin-A expression. We have found the manuscript of interest, and we would like to discuss why these results may be important from the clinical point of view. CKD patients develop atherosclerotic vascular disease earlier and faster than the general population. In CKD-induced cardiovascular disease, ‘‘classic” and ‘‘typical” risk factors of vascular calcification (VC) have to be considered. In fact, severe VC is a common event in CKD [2]. These patients develop extensive medial calcification, which causes increased arterial stiffness and elevated cardiovascular disease that induces higher morbidity and mortality. A mounting number of VC risk factors are involved in the dialysis population: age, gender, dialysis vintage, inflammation, mineral metabolism abnormalities, and diabetes [3]. In addition to these well-known features of CKD patients, new pathogenetic tools have emerged in the last decade in the nephrology community to allow a better understanding of the physiopathology of VC. In fact, although not completely elucidated, it is now clear that the process of calcification is not merely a passive deposition of calcium-phosphate crystals, but is a well ordinated process, involving cell activity and some specific protein synthesis [3]. Accordingly, several (bone related) proteins have now been identified as being capable of inducing or inhibiting the process of extraskeletal calcification and the potential role of the ‘‘protective” proteins associated with reduced VC in CKD needs to be better clarified. Human Fetuin-A (AHSG, a2-Heremans Schmid glycoprotein, a2HS-glycoprotein, a2-HSG) is an extracellular calcium-regulatory protein acting as a potent inhibitor of calcium-phosphate precipitation [4]. It is ubiquitous and accounts for more than 50% of the precipitation inhibitory effect of serum. The name Fetuin was given to the first fetal protein found in bovine serum in 1944. Fetuin-A is an important inhibitor of extraskeletal calcification. Similarly to other acute phase reaction proteins it is synthesized by the liver and its concentration falls during the cellular immunity-phase of inflammation [5]. In vitro, Fetuin-A inhibits the de novo formation and precipitation of calcium-phosphate, with no effects on hydroxyapatite once it is formed [5]. Fetuin-A antagonizes the antiproliferative action of TGFb1 and blocks osteogenesis and deposition of calcium-containing matrix in dexamethosone-treated rat bone marrow cells [4]. Fetuin-A knock-out mice develop extensive ectopic calcifications in myocardium, kidney, lung, tongue, and skin [4]. In addition, HD patients with lower serum Fetuin-A levels have increased mortality due to cardiovascular events [6]. This observation by Ketteler et al. [6] suggests that Fetuin-A is involved in pre1043-4666/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.cyto.2008.11.012
venting the accelerated extraskeletal calcification observed in CKD. It has been speculated that Fetuin-A is down-regulated in vivo as a negative acute-phase protein; its serum concentration, in fact, falls during inflammation or trauma [7]. According to this earlier observation, a significant inverse relationship was found in dialysis patients between Fetuin-A and C reactive protein (CRP) serum concentrations [7]. This hypothesis was also tested in a population of 115 HD patients, in which VC were associated with increasing age, a history of cardiovascular events and abnormal levels of inflammatory markers, such as reduction in Fetuin-A and albumin, and an increase in CRP and fibrinogen [8]. Furthermore, a recent study showed that primary human hepatocytes synthesize Fetuin-A and this synthesis is down-regulated by interleukin 6 [9], suggesting that this potent negative action of IL-6 might be counterbalanced in order to ameliorate cardiovascular disease in CKD patients. Price et al. [10] have thoroughly investigated the mechanisms by which proteins inhibit VC. They showed the existence of a high molecular weight complex of a calcium-phosphate mineral phase and the two inhibitory proteins Fetuin-A and matrix GLA protein (MGP) in the serum of rats treated with the bone-active bisphosphonate etidronate [10]. Furthermore, in a recent in vivo study, Price found that vitamin D-induced VC associates with a 70% reduction of serum Fetuin-A, probably due to the clearance of the Fetuin-A mineral complex from serum [11]. Although certainly associated with or pathogenetically involved in VC, no one substance can be defined as ‘‘the marker” of this important clinical condition. If we consider the complexity of the calcification process, this is not a surprise. However, available data indicate that a complex interplay among several ‘‘actors” is normally occurring at the tissue level to avoid pathologic deposition of crystals. We can speculate that, in the future, assessment of several markers like Fetuin-A, will enable us to recognize those patients or clinical conditions in which the bioactive process of calcification and inflammation is almost invariably triggered. References [1] Dervisoglu E, Kir HM, Kalender B, Caglayan C, Eraldemir C. Serum fetuin-A concentrations are inversely related to cytokine concentrations in patients with chronic renal failure. Cytokine, 13 October 2008 [Epub ahead of Print]. [2] Cozzolino M, Brancaccio D, Gallieni M, Slatopolsky E. Pathogenesis of vascular calcification in chronic kidney disease. Kidney Int 2005;68(2):429–36. [3] Cozzolino M, Mazzaferro S, Pugliese F, Brancaccio D. Vascular calcification and uremia: what do we know? Am J Nephrol 2008;28:339–46. [4] Schafer C, Heiss A, Schwarz A, et al. The serum protein a2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification. J Clin Invest 2003;112:357–66. [5] Heiss A, DuChesne A, Denecke B, et al. Structural basis of calcification inhibition by alpha 2-HS glycoprotein/fetuin-A. Formation of colloidal calciprotein particles. J Biol Chem 2003;278:13333–41. [6] Ketteler M, Bongartz P, Westenfeld R, et al. Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet 2003;361:827–33.
Letter / Cytokine 45 (2009) 70–71 [7] Lebreton JP, Joisel F. Serum concentration of human alpha2 HS glycoprotein during the inflammatory process. J Clin Invest 1979;64:1118–29. [8] Cozzolino M, Galassi A, Biondi ML, et al. Serum Fetuin-A levels as a link between inflammation and cardiovascular calcification in haemodialysis patients. Am J Nephrol 2006;26:423–9. [9] Memoli B, De Bartolo L, Favia P, et al. Fetuin-A gene expression, synthesis and release in primary human hepatocytes cultured in a galactosylated membrane bioreactor. Biomaterials 2007;28:4836–44. [10] Price PA, Lim JE. The inhibition of calcium phosphate precipitation by fetuin is accompanied by the formation of a fetuin–mineral complex. J Biol Chem 2003;278:22144–52.
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[11] Price PA, Williamson MK, Nguyen TM, Than TN. Serum levels of the fetuin– mineral complex correlate with artery calcification in the rat. J Biol Chem 2004;279:1594–600.
Mario Cozzolino *, Maurizio Gallieni, Diego Brancaccio Renal Division, S. Paolo Hospital, University of Milan, Via A. di Rudinì, 8, 20142 Milan, Italy E-mail address: [email protected] (M. Cozzolino)
* Corresponding author. Fax: +39 02 89129989.
Contents lists available at ScienceDirect
Cytokine journal homepage: www.elsevier.com/locate/issn/10434666
Letter Inflammation and vascular calcification in chronic kidney disease: The role of Fetuin-A In this Issue of the Journal, we read with interest the article by Dervisoglu et al. [1] on the negative association between serum Fetuin-A levels and concentrations of the inflammatory cytokines IL-1b, IL-6, and TNFa in chronic kidney disease (CKD) and haemodialysis (HD) patients. The authors’ results support the hypothesis of inflammation-dependent down-regulation of Fetuin-A expression. We have found the manuscript of interest, and we would like to discuss why these results may be important from the clinical point of view. CKD patients develop atherosclerotic vascular disease earlier and faster than the general population. In CKD-induced cardiovascular disease, ‘‘classic” and ‘‘typical” risk factors of vascular calcification (VC) have to be considered. In fact, severe VC is a common event in CKD [2]. These patients develop extensive medial calcification, which causes increased arterial stiffness and elevated cardiovascular disease that induces higher morbidity and mortality. A mounting number of VC risk factors are involved in the dialysis population: age, gender, dialysis vintage, inflammation, mineral metabolism abnormalities, and diabetes [3]. In addition to these well-known features of CKD patients, new pathogenetic tools have emerged in the last decade in the nephrology community to allow a better understanding of the physiopathology of VC. In fact, although not completely elucidated, it is now clear that the process of calcification is not merely a passive deposition of calcium-phosphate crystals, but is a well ordinated process, involving cell activity and some specific protein synthesis [3]. Accordingly, several (bone related) proteins have now been identified as being capable of inducing or inhibiting the process of extraskeletal calcification and the potential role of the ‘‘protective” proteins associated with reduced VC in CKD needs to be better clarified. Human Fetuin-A (AHSG, a2-Heremans Schmid glycoprotein, a2HS-glycoprotein, a2-HSG) is an extracellular calcium-regulatory protein acting as a potent inhibitor of calcium-phosphate precipitation [4]. It is ubiquitous and accounts for more than 50% of the precipitation inhibitory effect of serum. The name Fetuin was given to the first fetal protein found in bovine serum in 1944. Fetuin-A is an important inhibitor of extraskeletal calcification. Similarly to other acute phase reaction proteins it is synthesized by the liver and its concentration falls during the cellular immunity-phase of inflammation [5]. In vitro, Fetuin-A inhibits the de novo formation and precipitation of calcium-phosphate, with no effects on hydroxyapatite once it is formed [5]. Fetuin-A antagonizes the antiproliferative action of TGFb1 and blocks osteogenesis and deposition of calcium-containing matrix in dexamethosone-treated rat bone marrow cells [4]. Fetuin-A knock-out mice develop extensive ectopic calcifications in myocardium, kidney, lung, tongue, and skin [4]. In addition, HD patients with lower serum Fetuin-A levels have increased mortality due to cardiovascular events [6]. This observation by Ketteler et al. [6] suggests that Fetuin-A is involved in pre1043-4666/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.cyto.2008.11.012
venting the accelerated extraskeletal calcification observed in CKD. It has been speculated that Fetuin-A is down-regulated in vivo as a negative acute-phase protein; its serum concentration, in fact, falls during inflammation or trauma [7]. According to this earlier observation, a significant inverse relationship was found in dialysis patients between Fetuin-A and C reactive protein (CRP) serum concentrations [7]. This hypothesis was also tested in a population of 115 HD patients, in which VC were associated with increasing age, a history of cardiovascular events and abnormal levels of inflammatory markers, such as reduction in Fetuin-A and albumin, and an increase in CRP and fibrinogen [8]. Furthermore, a recent study showed that primary human hepatocytes synthesize Fetuin-A and this synthesis is down-regulated by interleukin 6 [9], suggesting that this potent negative action of IL-6 might be counterbalanced in order to ameliorate cardiovascular disease in CKD patients. Price et al. [10] have thoroughly investigated the mechanisms by which proteins inhibit VC. They showed the existence of a high molecular weight complex of a calcium-phosphate mineral phase and the two inhibitory proteins Fetuin-A and matrix GLA protein (MGP) in the serum of rats treated with the bone-active bisphosphonate etidronate [10]. Furthermore, in a recent in vivo study, Price found that vitamin D-induced VC associates with a 70% reduction of serum Fetuin-A, probably due to the clearance of the Fetuin-A mineral complex from serum [11]. Although certainly associated with or pathogenetically involved in VC, no one substance can be defined as ‘‘the marker” of this important clinical condition. If we consider the complexity of the calcification process, this is not a surprise. However, available data indicate that a complex interplay among several ‘‘actors” is normally occurring at the tissue level to avoid pathologic deposition of crystals. We can speculate that, in the future, assessment of several markers like Fetuin-A, will enable us to recognize those patients or clinical conditions in which the bioactive process of calcification and inflammation is almost invariably triggered. References [1] Dervisoglu E, Kir HM, Kalender B, Caglayan C, Eraldemir C. Serum fetuin-A concentrations are inversely related to cytokine concentrations in patients with chronic renal failure. Cytokine, 13 October 2008 [Epub ahead of Print]. [2] Cozzolino M, Brancaccio D, Gallieni M, Slatopolsky E. Pathogenesis of vascular calcification in chronic kidney disease. Kidney Int 2005;68(2):429–36. [3] Cozzolino M, Mazzaferro S, Pugliese F, Brancaccio D. Vascular calcification and uremia: what do we know? Am J Nephrol 2008;28:339–46. [4] Schafer C, Heiss A, Schwarz A, et al. The serum protein a2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification. J Clin Invest 2003;112:357–66. [5] Heiss A, DuChesne A, Denecke B, et al. Structural basis of calcification inhibition by alpha 2-HS glycoprotein/fetuin-A. Formation of colloidal calciprotein particles. J Biol Chem 2003;278:13333–41. [6] Ketteler M, Bongartz P, Westenfeld R, et al. Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet 2003;361:827–33.
Letter / Cytokine 45 (2009) 70–71 [7] Lebreton JP, Joisel F. Serum concentration of human alpha2 HS glycoprotein during the inflammatory process. J Clin Invest 1979;64:1118–29. [8] Cozzolino M, Galassi A, Biondi ML, et al. Serum Fetuin-A levels as a link between inflammation and cardiovascular calcification in haemodialysis patients. Am J Nephrol 2006;26:423–9. [9] Memoli B, De Bartolo L, Favia P, et al. Fetuin-A gene expression, synthesis and release in primary human hepatocytes cultured in a galactosylated membrane bioreactor. Biomaterials 2007;28:4836–44. [10] Price PA, Lim JE. The inhibition of calcium phosphate precipitation by fetuin is accompanied by the formation of a fetuin–mineral complex. J Biol Chem 2003;278:22144–52.
71
[11] Price PA, Williamson MK, Nguyen TM, Than TN. Serum levels of the fetuin– mineral complex correlate with artery calcification in the rat. J Biol Chem 2004;279:1594–600.
Mario Cozzolino *, Maurizio Gallieni, Diego Brancaccio Renal Division, S. Paolo Hospital, University of Milan, Via A. di Rudinì, 8, 20142 Milan, Italy E-mail address: [email protected] (M. Cozzolino)
* Corresponding author. Fax: +39 02 89129989.