A novel role of cellular interactions in vascular calcification

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Abstract

A series of clinical trials have confirmed the correlation between vascular calcification (VC) and cardiovascular events and mortality. However, current treatments have little effects on the regression of VC. Potent and illustrative mechanisms have been proven to exist in both bone metabolism and VC, indicating that these two processes share similarities in onset and progression. Multiple osteoblast-like cells and signaling pathways are involved in the process of VC. In this review, we summarized the roles of different osteoblast-like cells and we emphasized on how they communicated and interacted with each other using different signaling pathways. Further studies are needed to uncover the underlying mechanisms and to provide novel therapies for VC.

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Most cited references 56

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Role of the sodium-dependent phosphate cotransporter, Pit-1, in vascular smooth muscle cell calcification.

Xianwu Li, Hsueh-Ying Yang, Cecilia M. Giachelli (2006)

Vascular calcification is associated with cardiovascular morbidity and mortality. Hyperphosphatemia is an important contributor to vascular calcification. Our previous studies demonstrated that elevated phosphate induces calcification of smooth muscle cells (SMC) in vitro. Inhibition of phosphate transport by phosphonoformic acid blocked phosphate-induced calcification, implicating sodium-dependent phosphate cotransporters in this process. In the present study, we have investigated the role of the type III sodium-dependent phosphate cotransporter, Pit-1, in SMC calcification in vitro. Human SMC stably expressing Pit-1 small interfering double-stranded RNA (SMC-iRNA) were established using a retroviral system. SMC-iRNA had decreased Pit-1 mRNA and protein levels and sodium-dependent phosphate transport activity compared with the control transduced cells (SMC-CT) (2.9 versus 9.78 nmol/mg protein per 30 minutes, respectively). Furthermore, phosphate-induced SMC calcification was significantly inhibited in SMC-iRNA compared with SMC-CT at all time points examined. Overexpression of Pit-1 restored phosphate uptake and phosphate-induced calcification in Pit-1 deficient cells. Mechanistically, although Pit-1-mediated SMC calcification was not associated with apoptosis or cell-derived vesicles, inhibition of phosphate uptake in Pit-1 knockdown cells blocked the induction of the osteogenic markers Cbfa-1 and osteopontin. Our results indicate that phosphate uptake through Pit-1 is essential for SMC calcification and phenotypic modulation in response to elevated phosphate.

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Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals.

Joyce M Pingsterhaus, Hamish M A Towler, A D Loewy … (2005)

In diabetic LDLR-/- mice, an ectopic BMP2-Msx2 gene regulatory program is upregulated in association with vascular calcification. We verified the procalcific actions of aortic Msx2 expression in vivo. CMV-Msx2 transgenic (CMV-Msx2Tg(+)) mice expressed 3-fold higher levels of aortic Msx2 than nontransgenic littermates. On high-fat diets, CMV-Msx2Tg(+) mice exhibited marked cardiovascular calcification involving aortic and coronary tunica media. This corresponded to regions of Msx2 immunoreactivity in adjacent adventitial myofibroblasts, suggesting a potential paracrine osteogenic signal. To better understand Msx2-regulated calcification, we studied actions in 10T1/2 cells. We found that conditioned media from Msx2-transduced 10T1/2 cells (Msx2-CM) is both pro-osteogenic and adipostatic; these features are characteristic of Wnt signaling. Msx2-CM stimulated Wnt-dependent TCF/LEF transcription, and Msx2-transduced cells exhibited increased nuclear beta-catenin localization with concomitant alkaline phosphatase induction. Msx2 upregulated Wnt3a and Wnt7a but downregulated expression of the canonical inhibitor Dkk1. Dkk1 treatment reversed osteogenic and adipostatic actions of Msx2. Teriparatide, a PTH1R agonist that inhibits murine vascular calcification, suppressed vascular BMP2-Msx2-Wnt signaling. Analyses of CMV-Msx2Tg(+) mice confirmed that Msx2 suppresses aortic Dkk1 and upregulates vascular Wnts; moreover, TOPGAL(+) (Wnt reporter); CMV-Msx2Tg(+) mice exhibited augmented aortic LacZ expression. Thus, Msx2-expressing cells elaborated an osteogenic milieu that promotes vascular calcification in part via paracrine Wnt signals.

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Osteoprotegerin Reverses Osteoporosis by Inhibiting Endosteal Osteoclasts and Prevents Vascular Calcification by Blocking a Process Resembling Osteoclastogenesis

Hosung Min, Sean Morony, Ildiko Sarosi … (2000)

High systemic levels of osteoprotegerin (OPG) in OPG transgenic mice cause osteopetrosis with normal tooth eruption and bone elongation and inhibit the development and activity of endosteal, but not periosteal, osteoclasts. We demonstrate that both intravenous injection of recombinant OPG protein and transgenic overexpression of OPG in OPG−/2 mice effectively rescue the osteoporotic bone phenotype observed in OPG-deficient mice. However, intravenous injection of recombinant OPG over a 4-wk period could not reverse the arterial calcification observed in OPG−/− mice. In contrast, transgenic OPG delivered from mid-gestation through adulthood does prevent the formation of arterial calcification in OPG−/− mice. Although OPG is normally expressed in arteries, OPG ligand (OPGL) and receptor activator of NF-κB (RANK) are not detected in the arterial walls of wild-type adult mice. Interestingly, OPGL and RANK transcripts are detected in the calcified arteries of OPG−/− mice. Furthermore, RANK transcript expression coincides with the presence of multinuclear osteoclast-like cells. These findings indicate that the OPG/OPGL/RANK signaling pathway may play an important role in both pathological and physiological calcification processes. Such findings may also explain the observed high clinical incidence of vascular calcification in the osteoporotic patient population.

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Author and article information

Contributors

Adham Sameer A. Bardeesi: Bardeesi95@hotmail.com

Jingwei Gao: gaojw5@mail2.sysu.edu.cn

Kun Zhang: zszhangk@hotmail.com

Suntian Yu: sunty3@mail2.sysu.edu.cn

Mengchao Wei: wmcbs@126.com

Pinming Liu: liupm@mail.sysu.edu.cn

Hui Huang: 0086-20-81332475 , huangh8@mail.sysu.edu.cn

Journal

Journal ID (nlm-ta): J Transl Med

Journal ID (iso-abbrev): J Transl Med

Title: Journal of Translational Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1479-5876

Publication date (Electronic): 3 May 2017

Publication date PMC-release: 3 May 2017

Publication date Collection: 2017

Volume: 15

Electronic Location Identifier: 95

Affiliations

[1 ]ISNI 0000 0001 2360 039X, GRID grid.12981.33, Zhongshan Medical School, , Sun Yat-sen University, ; Guangzhou, China

[2 ]ISNI 0000 0001 2360 039X, GRID grid.12981.33, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Cardiology, Sun Yat-sen Memorial Hospital, , Sun Yat-sen University, ; 107 West Yanjiang Road, Guangzhou, 510120 China

[3 ]ISNI 0000 0001 2360 039X, GRID grid.12981.33, Laboratory of RNA and Major Diseases of Brain and Heart, Sun Yat-sen Memorial Hospital, , Sun Yat-sen University, ; Guangzhou, China

Article

Publisher ID: 1190

DOI: 10.1186/s12967-017-1190-z

PMC ID: 5414234

PubMed ID: 28464904

SO-VID: e50c44bd-b178-4ea1-a6db-c6769106edf6

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 28 December 2016

Date accepted : 20 April 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81670676

Award ID: 81422011

Award Recipient : Hui Huang

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China ;

Award ID: 81370837

Award Recipient : Hui Huang

Funded by: Natural Science Foundation of Guangdong Province

Award ID: 2014A030313035

Award Recipient : Hui Huang

Funded by: Guangzhou Science and Technology Project

Award ID: 2060404

Award Recipient : Hui Huang

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ScienceOpen disciplines: Medicine

Keywords: vascular calcification,osteoblast-like cells,autophagy,signaling pathways

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ScienceOpen disciplines: Medicine

Keywords: vascular calcification, osteoblast-like cells, autophagy, signaling pathways

A novel role of cellular interactions in vascular calcification

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Vascular Biology

Most cited references 56

Role of the sodium-dependent phosphate cotransporter, Pit-1, in vascular smooth muscle cell calcification.

Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals.

Osteoprotegerin Reverses Osteoporosis by Inhibiting Endosteal Osteoclasts and Prevents Vascular Calcification by Blocking a Process Resembling Osteoclastogenesis

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