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

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, β-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.

• Authors: 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
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 4961 (03 21 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 29563538 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Bmp2 protein, mouse
• Bone Morphogenetic Protein 2
• Extracellular Matrix Proteins
• Intracellular Signaling Peptides and Proteins
• Phosphates
• Proteins
• Pyrazoles
• Pyrimidines
• Smad Proteins
• Ucma protein, mouse
• dorsomorphin

Topics

• Animals
• Aorta (cytology, pathology)
• Atherosclerosis (pathology)
• Biomarkers (metabolism)
• Bone Morphogenetic Protein 2 (metabolism)
• Cells, Cultured
• Chondrogenesis (drug effects)
• Disease Models, Animal
• Extracellular Matrix Proteins
• Gene Expression Regulation (drug effects)
• Humans
• Intracellular Signaling Peptides and Proteins
• Mice
• Mice, Inbred C57BL
• Mice, Knockout, ApoE
• Muscle, Smooth, Vascular (cytology, pathology)
• Myocytes, Smooth Muscle (pathology)
• Phosphates (adverse effects)
• Plaque, Atherosclerotic (pathology)
• Primary Cell Culture
• Protein Binding
• Proteins (genetics, metabolism)
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• Signal Transduction (drug effects)
• Smad Proteins (metabolism)
• Vascular Calcification (chemically induced, pathology)