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Myeloid calcifying cells promote atherosclerotic calcification via paracrine activity and allograft inflammatory factor-1 overexpression

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Abstract

Several cell types contribute to atherosclerotic calcification. Myeloid calcifying cells (MCCs) are monocytes expressing osteocalcin (OC) and bone alkaline phosphatase (BAP). Herein, we tested whether MCCs promote atherosclerotic calcification in vivo. We show that the murine spleen contains OC+BAP+ cells with a phenotype similar to human MCCs, a high expression of adhesion molecules and CD11b, and capacity to calcify in vitro and in vivo. Injection of GFP+ OC+BAP+ cells into 8- or 40-week ApoE−/− mice led to more extensive calcifications in atherosclerotic areas after 24 or 4 weeks, respectively, compared to control OC−BAP− cells. Despite that OC+BAP+ cells had a selective transendothelial migration capacity, tracking of the GFP signal revealed that presence of injected cells within atherosclerotic areas was an extremely rare event and so GFP mRNA was undetectable by qPCR of lesion extracts. By converse, injected OC+BAP+ cells persisted in the bloodstream and bone marrow up to 24 weeks, suggesting a paracrine effect. Indeed, OC+BAP+ cell-conditioned medium (CM) promoted calcification by cultured vascular smooth muscle cells (VSMC) more than CM from OC−BAP− cells. A genomic and proteomic investigation of MCCs identified allograft inflammatory factor (AIF)-1 as a potential candidate of this paracrine activity. AIF-1 stimulated VSMC calcification in vitro and monocyte-specific (CD11b-driven) AIF-1 overexpression in ApoE−/− mice increased calcium content in atherosclerotic areas. In conclusion, we show that murine OC+BAP+ cells correspond to human MCCs and promote atherosclerotic calcification in ApoE−/− mice, through paracrine activity and modulation of resident cells by AIF-1 overexpression.

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Acknowledgments

GPF is supported by a European Foundation for the Study of Diabetes (EFSD)/AstraZeneca young investigator award.

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Authors and Affiliations

  1. Venetian Institute of Molecular Medicine, Padova, Italy

    Mattia Albiero, Lisa Menegazzo, Elisa Boscaro, Nicol Poncina, Kenneth Dyar, Stefano Ciciliot, Carlo Agostini, Angelo Avogaro & Gian Paolo Fadini

  2. Department of Medicine, University of Padova, Via Giustiniani, 2, 35100, Padova, Italy

    Marcello Rattazzi, Lisa Menegazzo, Roberta Cappellari, Elisa Pagnin, Elisa Bertacco, Nicol Poncina, Stefano Ciciliot, Carlo Agostini, Angelo Avogaro & Gian Paolo Fadini

  3. Department of Immunology, Kitasato School of Medicine, Tokyo, Japan

    Kazuya Iwabuchi

  4. Proteomic Center of Padova University, Padova, Italy

    Renato Millioni & Giorgio Arrigoni

  5. Department of Biomedical Sciences, University of Padova, Padova, Italy

    Giorgio Arrigoni

  6. Institute of Physiology, Cardiovascular Research, University of Zurich, Zurich, Switzerland

    Nicolle Kraenkel & Ulf Landmesser

  7. Department of Cardiology, University Hospital Zurich, Zurich, Switzerland

    Nicolle Kraenkel & Ulf Landmesser

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  1. Mattia Albiero
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  2. Marcello Rattazzi
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Correspondence to Gian Paolo Fadini.

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Albiero, M., Rattazzi, M., Menegazzo, L. et al. Myeloid calcifying cells promote atherosclerotic calcification via paracrine activity and allograft inflammatory factor-1 overexpression. Basic Res Cardiol 108, 368 (2013). https://doi.org/10.1007/s00395-013-0368-7

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