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Osteomodulin attenuates smooth muscle cell osteogenic transition in vascular calcification

Skenteris, Nikolaos T ; Seime, Till ; Witasp, Anna ; Karlöf, Eva ; Wasilewski, Grzegorz B ; Heuschkel, Marina A ; Jaminon, Armand M G ; Oduor, Loureen LU ; Dzhanaev, Robert and Kronqvist, Malin , et al. (2022) In Clinical and Translational Medicine 12(2). p.1-22
Abstract

RATIONALE: Vascular calcification is a prominent feature of late-stage diabetes, renal and cardiovascular disease (CVD), and has been linked to adverse events. Recent studies in patients reported that plasma levels of osteomodulin (OMD), a proteoglycan involved in bone mineralisation, associate with diabetes and CVD. We hypothesised that OMD could be implicated in these diseases via vascular calcification as a common underlying factor and aimed to investigate its role in this context.

METHODS AND RESULTS: In patients with chronic kidney disease, plasma OMD levels correlated with markers of inflammation and bone turnover, with the protein present in calcified arterial media. Plasma OMD also associated with cardiac calcification and... (More)

RATIONALE: Vascular calcification is a prominent feature of late-stage diabetes, renal and cardiovascular disease (CVD), and has been linked to adverse events. Recent studies in patients reported that plasma levels of osteomodulin (OMD), a proteoglycan involved in bone mineralisation, associate with diabetes and CVD. We hypothesised that OMD could be implicated in these diseases via vascular calcification as a common underlying factor and aimed to investigate its role in this context.

METHODS AND RESULTS: In patients with chronic kidney disease, plasma OMD levels correlated with markers of inflammation and bone turnover, with the protein present in calcified arterial media. Plasma OMD also associated with cardiac calcification and the protein was detected in calcified valve leaflets by immunohistochemistry. In patients with carotid atherosclerosis, circulating OMD was increased in association with plaque calcification as assessed by computed tomography. Transcriptomic and proteomic data showed that OMD was upregulated in atherosclerotic compared to control arteries, particularly in calcified plaques, where OMD expression correlated positively with markers of smooth muscle cells (SMCs), osteoblasts and glycoproteins. Immunostaining confirmed that OMD was abundantly present in calcified plaques, localised to extracellular matrix and regions rich in α-SMA+ cells. In vivo, OMD was enriched in SMCs around calcified nodules in aortic media of nephrectomised rats and in plaques from ApoE-/- mice on warfarin. In vitro experiments revealed that OMD mRNA was upregulated in SMCs stimulated with IFNγ, BMP2, TGFβ1, phosphate and β-glycerophosphate, and by administration of recombinant human OMD protein (rhOMD). Mechanistically, addition of rhOMD repressed the calcification process of SMCs treated with phosphate by maintaining their contractile phenotype along with enriched matrix organisation, thereby attenuating SMC osteoblastic transformation. Mechanistically, the role of OMD is exerted likely through its link with SMAD3 and TGFB1 signalling, and interplay with BMP2 in vascular tissues.

CONCLUSION: We report a consistent association of both circulating and tissue OMD levels with cardiovascular calcification, highlighting the potential of OMD as a clinical biomarker. OMD was localised in medial and intimal α-SMA+ regions of calcified cardiovascular tissues, induced by pro-inflammatory and pro-osteogenic stimuli, while the presence of OMD in extracellular environment attenuated SMC calcification.

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publication status
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subject
keywords
Analysis of Variance, Cohort Studies, Cross-Sectional Studies, Extracellular Matrix Proteins/metabolism, Humans, Linear Models, Muscle, Smooth/drug effects, Netherlands, Osteogenesis/genetics, Prospective Studies, Proteoglycans/metabolism, Statistics, Nonparametric, Sweden, Vascular Calcification/etiology
in
Clinical and Translational Medicine
volume
12
issue
2
article number
e682
pages
1 - 22
publisher
Wiley
external identifiers
  • pmid:35184400
ISSN
2001-1326
DOI
10.1002/ctm2.682
language
English
LU publication?
yes
additional info
© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
id
090ef030-78b8-46e8-ac80-fbbe164a1cad
date added to LUP
2022-06-02 08:43:56
date last changed
2022-06-03 02:22:15
@article{090ef030-78b8-46e8-ac80-fbbe164a1cad,
  abstract     = {{<p>RATIONALE: Vascular calcification is a prominent feature of late-stage diabetes, renal and cardiovascular disease (CVD), and has been linked to adverse events. Recent studies in patients reported that plasma levels of osteomodulin (OMD), a proteoglycan involved in bone mineralisation, associate with diabetes and CVD. We hypothesised that OMD could be implicated in these diseases via vascular calcification as a common underlying factor and aimed to investigate its role in this context.</p><p>METHODS AND RESULTS: In patients with chronic kidney disease, plasma OMD levels correlated with markers of inflammation and bone turnover, with the protein present in calcified arterial media. Plasma OMD also associated with cardiac calcification and the protein was detected in calcified valve leaflets by immunohistochemistry. In patients with carotid atherosclerosis, circulating OMD was increased in association with plaque calcification as assessed by computed tomography. Transcriptomic and proteomic data showed that OMD was upregulated in atherosclerotic compared to control arteries, particularly in calcified plaques, where OMD expression correlated positively with markers of smooth muscle cells (SMCs), osteoblasts and glycoproteins. Immunostaining confirmed that OMD was abundantly present in calcified plaques, localised to extracellular matrix and regions rich in α-SMA+ cells. In vivo, OMD was enriched in SMCs around calcified nodules in aortic media of nephrectomised rats and in plaques from ApoE-/- mice on warfarin. In vitro experiments revealed that OMD mRNA was upregulated in SMCs stimulated with IFNγ, BMP2, TGFβ1, phosphate and β-glycerophosphate, and by administration of recombinant human OMD protein (rhOMD). Mechanistically, addition of rhOMD repressed the calcification process of SMCs treated with phosphate by maintaining their contractile phenotype along with enriched matrix organisation, thereby attenuating SMC osteoblastic transformation. Mechanistically, the role of OMD is exerted likely through its link with SMAD3 and TGFB1 signalling, and interplay with BMP2 in vascular tissues.</p><p>CONCLUSION: We report a consistent association of both circulating and tissue OMD levels with cardiovascular calcification, highlighting the potential of OMD as a clinical biomarker. OMD was localised in medial and intimal α-SMA+ regions of calcified cardiovascular tissues, induced by pro-inflammatory and pro-osteogenic stimuli, while the presence of OMD in extracellular environment attenuated SMC calcification.</p>}},
  author       = {{Skenteris, Nikolaos T and Seime, Till and Witasp, Anna and Karlöf, Eva and Wasilewski, Grzegorz B and Heuschkel, Marina A and Jaminon, Armand M G and Oduor, Loureen and Dzhanaev, Robert and Kronqvist, Malin and Lengquist, Mariette and Peeters, Frederique E C M and Söderberg, Magnus and Hultgren, Rebecka and Roy, Joy and Maegdefessel, Lars and Arnardottir, Hildur and Bengtsson, Eva and Goncalves, Isabel and Quertermous, Thomas and Goettsch, Claudia and Stenvinkel, Peter and Schurgers, Leon J and Matic, Ljubica}},
  issn         = {{2001-1326}},
  keywords     = {{Analysis of Variance; Cohort Studies; Cross-Sectional Studies; Extracellular Matrix Proteins/metabolism; Humans; Linear Models; Muscle, Smooth/drug effects; Netherlands; Osteogenesis/genetics; Prospective Studies; Proteoglycans/metabolism; Statistics, Nonparametric; Sweden; Vascular Calcification/etiology}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{1--22}},
  publisher    = {{Wiley}},
  series       = {{Clinical and Translational Medicine}},
  title        = {{Osteomodulin attenuates smooth muscle cell osteogenic transition in vascular calcification}},
  url          = {{http://dx.doi.org/10.1002/ctm2.682}},
  doi          = {{10.1002/ctm2.682}},
  volume       = {{12}},
  year         = {{2022}},
}