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      Wnt signaling contributes to vascular calcification by induction of matrix metalloproteinases

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          Abstract

          Background

          Vascular calcifications such as arteriosclerosis, which is characterized by a calcificiation of the tunica media, represent major comorbidities e.g. in patients with chronic kidney disease (CKD). An essential step during the development of arteriosclerosis is the transdifferentiation/calcification of vascular smooth muscle cells (VSMC) resembling osteogenesis. The matrix metalloproteinases (MMP)-2 and −9 were shown to promote these VSMC calcifications and their inhibition is of therapeutic value to prevent arteriosclerosis in preclinical studies. Aiming for an understanding of the underlying regulatory mechanisms of MMPs we here investigated, if the MMP-mediated VSMC calcification involves altered signaling of the Wnt pathway, which is known to impact osteogenesis.

          Methods

          We used an experimental in vitro model of vascular calcification. Transdifferentiation/calcification of murine VSMC was induced by elevated calcium and phosphorus levels. Calcification was assessed by calcium and alkaline phosphatase measurements. Activation/activity of the gelatinases MMP-2 and MMP-9 was assessed by conversion of fluorescence-labelled substrates. Activation of the Wnt pathway was analysed by a reporter gene assay.

          Results

          Besides pro-calcifying culture conditions, also activation of Wnt signaling by a specific agonist (under normal culture conditions) stimulated VSMC-calcification accompanied by enhanced expression and secretion of the gelatinases MMP-2 and −9. Vice versa, recombinant MMP-2 and −9 induced a time-delayed activation of Wnt signaling after 72 h in VSMC but showed no direct effects after 24–48 h. These effects were blocked by pharmacological inhibition of MMPs or of Wnt signaling.

          Conclusions

          Our study suggests that the pro-calcifying environment in CKD induces Wnt signaling in VSMC which in turn contributes to the induction of MMPs which then foster the development of arteriosclerosis. Thus, besides MMP inhibition, the inhibition of Wnt signaling in VSMC might represent a therapeutic target for the prevention of vascular calcifications.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12872-016-0362-8) contains supplementary material, which is available to authorized users.

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          Most cited references18

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          Vascular calcification: the killer of patients with chronic kidney disease.

          Eduardo Slatopolsky, Dwight Towler, Masahide Mizobuchi (2009)
          Cardiovascular complications are the leading cause of death in patients with chronic kidney disease (CKD). Vascular calcification is a common complication in CKD, and investigators have demonstrated that the extent and histoanatomic type of vascular calcification are predictors of subsequent vascular mortality. Although research efforts in the past decade have greatly improved our knowledge of the multiple factors and mechanisms involved in vascular calcification in patients with kidney disease, many questions remain unanswered. No longer can we accept the concept that vascular calcification in CKD is a passive process resulting from an elevated calcium-phosphate product. Rather, as a result of the metabolic insults of diabetes, dyslipidemia, oxidative stress, uremia, and hyperphosphatemia, "osteoblast-like" cells form in the vessel wall. These mineralizing cells as well as the recruitment of undifferentiated progenitors to the osteochondrocyte lineage play a critical role in the calcification process. Important transcription factors such as Msx 2, osterix, and RUNX2 are crucial in the programming of osteogenesis. Thus, the simultaneous increase in arterial osteochondrocytic programs and reduction in active cellular defense mechanisms creates the "perfect storm" of vascular calcification seen in ESRD. Innovative clinical studies addressing the combined use of inhibitors that work on vascular calcification through distinct molecular mechanisms, such as fetuin-A, osteopontin, and bone morphogenic protein 7, among others, will be necessary to reduce significantly the accrual of vascular calcifications and cardiovascular mortality in kidney disease. In addition, the roles of oxidative stress and inflammation on the fate of smooth muscle vascular cells and their function deserve further translational investigation.
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            Abdominal aortic calcific deposits are an important predictor of vascular morbidity and mortality.

            L Kauppila, L. Adrienne Cupples, J Polák … (2001)
            The impact of abdominal arterial calcific deposits on the prediction of cardiovascular disease (CVD) over a long follow-up interval deserves greater scrutiny. Lateral lumbar radiographs were studied as a predictor of incident coronary heart disease (CHD), CVD, and CVD mortality in 1049 men and 1466 women (mean age, 61 years) who were followed from 1967 to 1989. Anterior and posterior wall calcific deposits in the aorta at the level of the first through fourth lumbar vertebrae were graded according to increasing severity using a previously validated rating scale for abdominal aortic calcium (AAC) that ranges from 0 to 24 points. There were 454 cases of CHD, 709 cases of CVD, and 365 CVD deaths. Proportional hazards logistic regression was used to test for associations between AAC and later events after adjustment for age, cigarette use, diabetes mellitus, systolic blood pressure, left ventricular hypertrophy, body mass index, cholesterol, and HDL cholesterol. In comparisons with the lowest AAC tertile, the multivariate age-adjusted relative risks (RR) for CVD were increased in tertile 2 (men: RR, 1.33; 95% confidence interval [CI], 1.02 to 1.74; women: RR, 1.25; 95% CI, 0.95 to 1.65) and tertile 3 (men: RR, 1.68; 95% CI, 1.25 to 2.27; women: RR, 1.78; 95% CI, 1.33 to 2.38). Similar results were obtained with CHD and CVD mortality. AAC deposits, detected by lateral lumbar radiograms, are a marker of subclinical atherosclerotic disease and an independent predictor of subsequent vascular morbidity and mortality.
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              Wnt 3a promotes proliferation and suppresses osteogenic differentiation of adult human mesenchymal stem cells.

              Rocky S Tuan, D. Hall, Geraldine Perkins … (2004)
              Multipotential adult mesenchymal stem cells (MSCs) are able to differentiate along several known lineages, and lineage commitment is tightly regulated through specific cellular mediators and interactions. Recent observations of a low/high bone-mass phenotype in patients expressing a loss-/gain-of-function mutation in LRP5, a coreceptor of the Wnt family of signaling molecules, suggest the importance of Wnt signaling in bone formation, possibly involving MSCs. To analyze the role of Wnt signaling in mesenchymal osteogenesis, we have profiled the expression of WNTs and their receptors, FRIZZLEDs (FZDs), and several secreted Wnt inhibitors, such as SFRPs, and examined the effect of Wnt 3a, as a representative canonical Wnt member, during MSC osteogenesis in vitro. WNT11, FZD6, SFRP2, and SFRP3 are upregulated during MSC osteogenesis, while WNT9A and FZD7 are downregulated. MSCs also respond to exogenous Wnt 3a, based on increased beta-catenin nuclearization and activation of a Wnt-responsive promoter, and the magnitude of this response depends on the MSC differentiation state. Wnt 3a exposure inhibits MSC osteogenic differentiation, with decreased matrix mineralization and reduced alkaline phosphatase mRNA and activity. Wnt 3a treatment of fully osteogenically differentiated MSCs also suppresses osteoblastic marker gene expression. The Wnt 3a effect is accompanied by increased cell number, resulting from both increased proliferation and decreased apoptosis, particularly during expansion of undifferentiated MSCs. The osteo-suppressive effects of Wnt 3a are fully reversible, i.e., treatment prior to osteogenic induction does not compromise subsequent MSC osteogenesis. The results also showed that sFRP3 treatment attenuates some of the observed Wnt 3a effects on MSCs, and that inhibition of canonical Wnt signaling using a dominant negative TCF1 enhances MSC osteogenesis. Interestingly, expression of Wnt 5a, a non-canonical Wnt member, appeared to promote osteogenesis. Taken together, these findings suggest that canonical Wnt signaling functions in maintaining an undifferentiated, proliferating progenitor MSC population, whereas non-canonical Wnts facilitate osteogenic differentiation. Release from canonical Wnt regulation is a prerequisite for MSC differentiation. Thus, loss-/gain-of-function mutations of LRP5 would perturb Wnt signaling and depress/promote bone formation by affecting the progenitor cell pool. Elucidating Wnt regulation of MSC differentiation is important for their potential application in tissue regeneration. Copyright 2004 Wiley-Liss, Inc.
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                Author and article information

                Contributors
                Christian Freise:
                ORCID: http://orcid.org/0000-0003-2602-226X
                +4930450-525294 , christian.freise@charite.de
                Nadja Kretzschmar: Nadja.kretzschmar@charite.de
                Uwe Querfeld: uwe.querfeld@charite.de
                Journal
                Journal ID (nlm-ta): BMC Cardiovasc Disord
                Journal ID (iso-abbrev): BMC Cardiovasc Disord
                Title: BMC Cardiovascular Disorders
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1471-2261
                Publication date (Electronic): 30 September 2016
                Publication date PMC-release: 30 September 2016
                Publication date Collection: 2016
                Volume: 16
                Electronic Location Identifier: 185
                Affiliations
                [1 ]Center for Cardiovascular Research, Charité - University Medicine, Campus Mitte, Hessische Str. 3-4, 10115 Berlin, Germany
                [2 ]Department of Pediatric Nephrology, Charité - University Medicine, Campus Virchow Clinic, 13353 Berlin, Germany
                Author information
                http://orcid.org/0000-0003-2602-226X
                Article
                Publisher ID: 362
                DOI: 10.1186/s12872-016-0362-8
                PMC ID: 5045611
                SO-VID: 7739b616-17bf-45e5-a324-7abc4d633e1d
                Copyright © © The Author(s). 2016
                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 : 15 October 2015
                Date accepted : 27 September 2016
                Categories
                Subject: Research Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2016

                ScienceOpen disciplines: Cardiovascular Medicine
                Keywords: matrix metalloproteinases,vascular calcification,chronic kidney disease,vascular smooth muscle cells,wnt pathway,movas-1
                Data availability:
                ScienceOpen disciplines: Cardiovascular Medicine
                Keywords: matrix metalloproteinases, vascular calcification, chronic kidney disease, vascular smooth muscle cells, wnt pathway, movas-1

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