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BMP9 is produced by hepatocytes and circulates mainly in an active mature form complexed to its prodomain

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An Erratum to this article was published on 31 July 2011

Abstract

Bone Morphogenetic Protein 9 (BMP9) has been recently found to be the physiological ligand for the activin receptor-like kinase 1 (ALK1), and to be a major circulating vascular quiescence factor. Moreover, a soluble chimeric ALK1 protein (ALK1-Fc) has recently been developed and showed powerful anti-tumor growth and anti-angiogenic effects. However, not much is known concerning BMP9. This prompted us to investigate the human endogenous sources of this cytokine and to further characterize its circulating form(s) and its function. Analysis of BMP9 expression reveals that BMP9 is produced by hepatocytes and intrahepatic biliary epithelial cells. Gel filtration analysis combined with ELISA and biological assays demonstrate that BMP9 circulates in plasma (1) as an unprocessed inactive form that can be further activated by furin a serine endoprotease, and (2) as a mature and fully active form (composed of the mature form associated with its prodomain). Analysis of BMP9 circulating levels during mouse development demonstrates that BMP9 peaks during the first 3 weeks after birth and then decreases to 2 ng/mL in adulthood. We also show that circulating BMP9 physiologically induces a constitutive Smad1/5/8 phosphorylation in endothelial cells. Taken together, our results argue for the role of BMP9 as a hepatocyte-derived factor, circulating in inactive (40%) and active (60%) forms, the latter constantly activating endothelial cells to maintain them in a resting state.

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Acknowledgments

We thank Dr T. Jaffredo (CNRS and UPMC, UMR7622, Laboratoire de Biologie du Développement, Paris, France) who provided us with mouse embryonic plasma at E9.5.

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Authors and Affiliations

  1. Unit 1036, Biology of Cancer and Infection, INSERM, 17 rue des Martyrs, 38054, Grenoble, France

    Marie Bidart, Nicolas Ricard, Sandrine Levet, Christine Mallet, Laurent David, Mariela Subileau, Emmanuelle Tillet, Jean-Jacques Feige & Sabine Bailly

  2. UJF-Grenoble 1, Biology of Cancer and Infection, 38041, Grenoble, France

    Marie Bidart, Nicolas Ricard, Sandrine Levet, Christine Mallet, Laurent David, Mariela Subileau, Emmanuelle Tillet, Jean-Jacques Feige & Sabine Bailly

  3. CEA, DSV/iRTSV, Biology of Cancer and Infection, 38054, Grenoble, France

    Marie Bidart, Nicolas Ricard, Sandrine Levet, Christine Mallet, Laurent David, Mariela Subileau, Emmanuelle Tillet, Jean-Jacques Feige & Sabine Bailly

  4. Pôle Recherche, Centre Hospitalier Universitaire de Grenoble, 38043, Grenoble, France

    Marie Bidart

  5. U620/EA 4427 SeRAIC, INSERM, Université Rennes 1, 35043, Rennes, France

    Michel Samson

  6. Center for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada

    Laurent David

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  1. Marie Bidart
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Correspondence to Sabine Bailly.

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An erratum to this article can be found at http://dx.doi.org/10.1007/s00018-011-0776-5

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Bidart, M., Ricard, N., Levet, S. et al. BMP9 is produced by hepatocytes and circulates mainly in an active mature form complexed to its prodomain. Cell. Mol. Life Sci. 69, 313–324 (2012). https://doi.org/10.1007/s00018-011-0751-1

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