The matrix metalloproteinases 2 and 9 initiate uraemic vascular calcifications.
The matrix metalloproteinases (MMP) MMP-2 and MMP-9 are physiological regulators of vascular remodelling. Their dysregulation could contribute to vascular calcification. We examined the role of the MMP-2 and MMP-9 in uraemic vascular calcification in vivo and in vitro.



The impact of pharmacological MMP inhibition on the development of media calcifications was explored in an aggressive animal model of uraemic calcification. In addition, the selective effects of addition and inhibition, respectively, of MMP-2 and MMP-9 on calcium-/phosphate-induced calcifications were studied in a murine cell line of vascular smooth muscle cells (VSMCs).



High-dose calcitriol treatment of uraemic rats given a high phosphate diet induced massive calcifications, apoptosis and increased gene expressions of MMP-2, MMP-9 and of osteogenic transcription factors and proteins in aortic VSMC. The MMP inhibitor doxycycline prevented the VSMC transdifferentiation to osteoblastic cells, suppressed transcription of mediators of matrix remodelling and almost completely blocked aortic calcifications while further increasing apoptosis. Similarly, specific inhibitors of either MMP-2 or -9, or of both gelatinases (Ro28-2653) and a selective knockdown of MMP-2/-9 mRNA expression blocked calcification of murine VSMC induced by calcification medium (CM). In contrast to MMP inhibition, recombinant MMP-2 or MMP-9 enhanced CM-induced calcifications and the secretion of gelatinases.



These data indicate that both gelatinases provide essential signals for phenotypic VSMC conversion, matrix remodelling and the initiation of vascular calcification. Their inhibition seems a promising strategy in the prevention of vascular calcifications.
Center for Cardiovascular Research, Charité-University Medicine, Campus Mitte, Berlin, Germany Department of Pediatric Nephrology, Charité-University Medicine, Campus Virchow Clinic, Berlin, Germany.
Eva
E
Hecht
Center for Cardiovascular Research, Charité-University Medicine, Campus Mitte, Berlin, Germany Department of Pediatric Nephrology, Charité-University Medicine, Campus Virchow Clinic, Berlin, Germany.
Christian
C
Freise
Institute of Nutritional Science, University of Potsdam, Potsdam-Rehbrücke, Germany.
Karoline V
KV
Websky
Center for Cardiovascular Research, Charité-University Medicine, Campus Mitte, Berlin, Germany Department of Pediatric Nephrology, Charité-University Medicine, Campus Virchow Clinic, Berlin, Germany.
Hamoud
H
Nasser
Center for Cardiovascular Research, Charité-University Medicine, Campus Mitte, Berlin, Germany Department of Pediatric Nephrology, Charité-University Medicine, Campus Virchow Clinic, Berlin, Germany.
Nadja
N
Kretzschmar
Center for Cardiovascular Research, Charité-University Medicine, Campus Mitte, Berlin, Germany Department of Medicine and Cardiology, German Heart Institute, Berlin, Germany.
Philipp
P
Stawowy
Institute of Nutritional Science, University of Potsdam, Potsdam-Rehbrücke, Germany.
Berthold
B
Hocher
Center for Cardiovascular Research, Charité-University Medicine, Campus Mitte, Berlin, Germany Department of Pediatric Nephrology, Charité-University Medicine, Campus Virchow Clinic, Berlin, Germany.
Uwe
U
Querfeld
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D054338:Cell Transdifferentiation / Q000187:drug effects; D002478:Cells, Cultured; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D010012:Osteogenesis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014511:Uremia / Q000503:physiopathology*; D061205:Vascular Calcification / Q000503:physiopathology*
D061965:Matrix Metalloproteinase Inhibitors; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat
chronic kidney disease; matrix metalloproteinases; vascular calcification; vascular smooth muscle cells