title: Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (CKD).
abstract: BACKGROUND
  The majority of patients with chronic kidney disease (CKD) have excessive vascular calcification; however, most studies demonstrate that a subset of CKD patients do not have, nor develop, vascular calcification despite similar exposure to the uremic environment. This suggests protective mechanisms, or naturally occurring inhibitors, of calcification may be important.
  
  
  METHODS
  In order to determine the role of three inhibitors, fetuin-A, matrix gla protein (MGP), and osteoprotegerin (OPG) in the vascular calcification observed in patients with CKD-5, we (1) measured serum levels of these inhibitors and compared the levels to calcification assessed by computed tomography (CT); (2) examined arteries from CKD-5 patients by immunostaining for these inhibitors; and (3) examined the expression and effect of these inhibitors in cultured bovine vascular smooth muscle cells (BVSMCs) incubated in serum pooled from uremic patients compared to healthy controls.
  
  
  RESULTS
  There was a negative correlation of coronary artery calcification scores with serum fetuin-A levels (r=-0.30, P= 0.034) and a positive association with OPG levels (r= 0.29, P= 0.045). There was increasing immunostaining for both fetuin-A and MGP in arteries with increasing calcification graded semiquantitatively (P < 0.003). In vitro, fetuin-A added to mineralizing BVSMCs inhibited mineralization (P < 0.001). Compared to normal serum, BVSMCs incubated with uremic serum had a progressive increase in MGP expression with mineralization (P < 0.001) and increased expression of OPG in BVSMCs (P < 0.04).
  
  
  CONCLUSIONS
  These data demonstrate that fetuin-A, OPG, and MGP play an important role in the pathogenesis of uremic vascular calcification.
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. smoe@iupui.edu
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Moe
authors.forename: Martina
authors.initials: M
authors.lastname: Reslerova
authors.forename: Markus
authors.initials: M
authors.lastname: Ketteler
authors.forename: Kalisha
authors.initials: K
authors.lastname: O'neill
authors.forename: Danxia
authors.initials: D
authors.lastname: Duan
authors.forename: Jacob
authors.initials: J
authors.lastname: Koczman
authors.forename: Ralf
authors.initials: R
authors.lastname: Westenfeld
authors.forename: Willi
authors.initials: W
authors.lastname: Jahnen-Dechent
authors.forename: Neal X
authors.initials: NX
authors.lastname: Chen
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000032:analysis / Q000502:physiology*; D002114:Calcinosis / Q000209:etiology*; D002135:Calcium-Binding Proteins / Q000097:blood / Q000502:physiology*; D002417:Cattle; D002478:Cells, Cultured; D002908:Chronic Disease; D016326:Extracellular Matrix Proteins / Q000097:blood / Q000502:physiology*; D006023:Glycoproteins / Q000097:blood / Q000502:physiology*; D006801:Humans; D007674:Kidney Diseases / Q000150:complications*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear / Q000097:blood / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood / Q000502:physiology*; D014652:Vascular Diseases / Q000209:etiology*; D060749:alpha-2-HS-Glycoprotein; D000097568:Matrix Gla Protein
chemical_list: D001798:Blood Proteins; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D060749:alpha-2-HS-Glycoprotein; D000097568:Matrix Gla Protein; C556354:AHSG protein, human; C506030:TNFRSF11B protein, human