Ucma/GRP inhibits phosphate-induced vascular smooth muscle cell calcification via SMAD-dependent BMP signalling

Brecht A. Willems, Malgorzata Furmanik, Marjolein M. J. Caron, Martijn L. L. Chatrou, Dennis H. M. Kusters, Tim J. M. Welting, Michael Stock, Marta S. Rafael, Carla S. B. Viegas, Dina C. Simes, Cees Vermeer, Chris P. M. Reutelingsperger, Leon J. Schurgers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

35 Citations (Web of Science)

Abstract

Vascular calcification (VC) is the process of deposition of calcium phosphate crystals in the blood vessel wall, with a central role for vascular smooth muscle cells (VSMCs). VC is highly prevalent in chronic kidney disease (CKD) patients and thought, in part, to be induced by phosphate imbalance. The molecular mechanisms that regulate VC are not fully known. Here we propose a novel role for the mineralisation regulator Ucma/GRP (Upper zone of growth plate and Cartilage Matrix Associated protein/Gla Rich Protein) in phosphate-induced VSMC calcification. We show that Ucma/GRP is present in calcified atherosclerotic plaques and highly expressed in calcifying VSMCs in vitro. VSMCs from Ucma/GRP(-/-) mice showed increased mineralisation and expression of osteo/chondrogenic markers (BMP-2, Runx2, beta-catenin, p-SMAD1/5/8, ALP, OCN), and decreased expression of mineralisation inhibitor MGP, suggesting that Ucma/GRP is an inhibitor of mineralisation. Using BMP signalling inhibitor noggin and SMAD1/5/8 signalling inhibitor dorsomorphin we showed that Ucma/GRP is involved in inhibiting the BMP-2-SMAD1/5/8 osteo/chondrogenic signalling pathway in VSMCs treated with elevated phosphate concentrations. Additionally, we showed for the first time evidence of a direct interaction between Ucma/GRP and BMP-2. These results demonstrate an important role of Ucma/GRP in regulating osteo/chondrogenic differentiation and phosphate-induced mineralisation of VSMCs.
Original languageEnglish
Article number4961
Number of pages11
JournalScientific Reports
Volume8
DOIs
Publication statusPublished - 21 Mar 2018

Keywords

  • CHRONIC KIDNEY-DISEASE
  • GLA-RICH PROTEIN
  • HUMAN ATHEROSCLEROTIC PLAQUES
  • VITAMIN-K
  • PHENOTYPIC MODULATION
  • BONE-FORMATION
  • EXPRESSION
  • MINERALIZATION
  • DIFFERENTIATION
  • CARBOXYLATION

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