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

doi:10.1038/s41598-018-23353-y

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 journal › Article › Academic › peer-review

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 language	English
Article number	4961
Number of pages	11
Journal	Scientific Reports
Volume	8
DOIs	https://doi.org/10.1038/s41598-018-23353-y
Publication status	Published - 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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Willems, B. A., Furmanik, M., Caron, M. M. J., Chatrou, M. L. L., Kusters, D. H. M., Welting, T. J. M., Stock, M., Rafael, M. S., Viegas, C. S. B., Simes, D. C., Vermeer, C., Reutelingsperger, C. P. M., & Schurgers, L. J. (2018). Ucma/GRP inhibits phosphate-induced vascular smooth muscle cell calcification via SMAD-dependent BMP signalling. Scientific Reports, 8, Article 4961. https://doi.org/10.1038/s41598-018-23353-y

@article{0ee51a21933b4c0a9b516f4ddbcd068e,

title = "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, 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.",

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

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

year = "2018",

month = mar,

day = "21",

doi = "10.1038/s41598-018-23353-y",

language = "English",

volume = "8",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

}

Willems, BA, Furmanik, M, Caron, MMJ, Chatrou, MLL, Kusters, DHM, Welting, TJM, Stock, M, Rafael, MS, Viegas, CSB, Simes, DC, Vermeer, C, Reutelingsperger, CPM & Schurgers, LJ 2018, 'Ucma/GRP inhibits phosphate-induced vascular smooth muscle cell calcification via SMAD-dependent BMP signalling', Scientific Reports, vol. 8, 4961. https://doi.org/10.1038/s41598-018-23353-y

TY - JOUR

T1 - Ucma/GRP inhibits phosphate-induced vascular smooth muscle cell calcification via SMAD-dependent BMP signalling

AU - Willems, Brecht A.

AU - Furmanik, Malgorzata

AU - Caron, Marjolein M. J.

AU - Chatrou, Martijn L. L.

AU - Kusters, Dennis H. M.

AU - Welting, Tim J. M.

AU - Stock, Michael

AU - Rafael, Marta S.

AU - Viegas, Carla S. B.

AU - Simes, Dina C.

AU - Vermeer, Cees

AU - Reutelingsperger, Chris P. M.

AU - Schurgers, Leon J.

PY - 2018/3/21

Y1 - 2018/3/21

N2 - 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.

AB - 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.

KW - CHRONIC KIDNEY-DISEASE

KW - GLA-RICH PROTEIN

KW - HUMAN ATHEROSCLEROTIC PLAQUES

KW - VITAMIN-K

KW - PHENOTYPIC MODULATION

KW - BONE-FORMATION

KW - EXPRESSION

KW - MINERALIZATION

KW - DIFFERENTIATION

KW - CARBOXYLATION

U2 - 10.1038/s41598-018-23353-y

DO - 10.1038/s41598-018-23353-y

M3 - Article

C2 - 29563538

SN - 2045-2322

VL - 8

JO - Scientific Reports

JF - Scientific Reports

M1 - 4961

ER -