TY - JOUR
T1 - Novel insights into osteogenesis and matrix remodelling associated with calcific uraemic arteriolopathy
AU - Kramann, Rafael
AU - Brandenburg, Vincent M.
AU - Schurgers, Leon J.
AU - Ketteler, Markus
AU - Westphal, Saskia
AU - Leisten, Isabelle
AU - Bovi, Manfred
AU - Jahnen-Dechent, Willi
AU - Knuechel, Ruth
AU - Floege, Juergen
AU - Schneider, Rebekka K.
PY - 2013/4
Y1 - 2013/4
N2 - Calcific uraemic arteriolopathy (CUA) or calciphylaxis is a rare, life-threatening disease predominantly occurring in patients with end-stage renal disease. Its pathogenesis has been suggested to include ectopic osteogenesis in soft tissue and the vasculature associated with extracellular matrix (ECM) remodelling. To gain further insights into the pathogenesis of CUA, we performed systematic analyses of skin specimens obtained from seven CUA patients including histology, immunohistochemistry, electron microscopy, electron dispersive X-ray analysis (EDX) and quantitative real-time RT-PCR. Skin specimens of (i) seven patients without chronic kidney disease and without CUA and (ii) seven dialysis patients without CUA served as controls. In the CUA skin lesions, we observed a significant upregulation of bone morphogenic protein 2 (BMP-2), its target gene Runx2 and its indirect antagonist sclerostin. Furthermore, we detected an increased expression of inactive uncarboxylated matrix Gla protein (Glu-MGP). The upregulation of osteogenesis-associated markers was accompanied by an increased expression of osteopontin, fibronectin, laminin and collagen I indicating an extensive remodelling of the subcutaneous ECM. EDX analysis revealed calcium/phosphate accumulations in the subcutis of all CUA patients with a molar ratio of 1.68 0.06 matching that of hydroxyapatite mineral. Widespread media calcification in cutaneous arterioles was associated with destruction of the endothelial layer and partial exfoliation of the endothelial cells (ECs). CD31 immunostaining revealed aggregates of ECs contributing to intraluminal obstruction and consecutive malperfusion resulting in the clinical picture of ulcerative necrosis in all seven patients. Our data indicate that CUA is an active osteogenic process including the upregulation of BMP-2 signalling, hydroxyapatite deposition and extensive matrix remodelling of the subcutis.
AB - Calcific uraemic arteriolopathy (CUA) or calciphylaxis is a rare, life-threatening disease predominantly occurring in patients with end-stage renal disease. Its pathogenesis has been suggested to include ectopic osteogenesis in soft tissue and the vasculature associated with extracellular matrix (ECM) remodelling. To gain further insights into the pathogenesis of CUA, we performed systematic analyses of skin specimens obtained from seven CUA patients including histology, immunohistochemistry, electron microscopy, electron dispersive X-ray analysis (EDX) and quantitative real-time RT-PCR. Skin specimens of (i) seven patients without chronic kidney disease and without CUA and (ii) seven dialysis patients without CUA served as controls. In the CUA skin lesions, we observed a significant upregulation of bone morphogenic protein 2 (BMP-2), its target gene Runx2 and its indirect antagonist sclerostin. Furthermore, we detected an increased expression of inactive uncarboxylated matrix Gla protein (Glu-MGP). The upregulation of osteogenesis-associated markers was accompanied by an increased expression of osteopontin, fibronectin, laminin and collagen I indicating an extensive remodelling of the subcutaneous ECM. EDX analysis revealed calcium/phosphate accumulations in the subcutis of all CUA patients with a molar ratio of 1.68 0.06 matching that of hydroxyapatite mineral. Widespread media calcification in cutaneous arterioles was associated with destruction of the endothelial layer and partial exfoliation of the endothelial cells (ECs). CD31 immunostaining revealed aggregates of ECs contributing to intraluminal obstruction and consecutive malperfusion resulting in the clinical picture of ulcerative necrosis in all seven patients. Our data indicate that CUA is an active osteogenic process including the upregulation of BMP-2 signalling, hydroxyapatite deposition and extensive matrix remodelling of the subcutis.
KW - bone morphogenic protein 2
KW - calciphylaxis
KW - matrix Gla protein
KW - matrix remodelling
KW - sclerostin
U2 - 10.1093/ndt/gfs466
DO - 10.1093/ndt/gfs466
M3 - Article
C2 - 23223222
SN - 0931-0509
VL - 28
SP - 856
EP - 868
JO - Nephrology Dialysis Transplantation
JF - Nephrology Dialysis Transplantation
IS - 4
ER -