Physiological and pathological function of vitamin K and γ-carboxylation:

The only known biological function of vitamin K is to serve as a co-factor for the γ-glutamyl carboxylase (GGCX), an enzyme responsible for the conversion of glutamic acid residues (GLU) into γ-carboxyglutamic acid (GLA) residues in specific secreted proteins. This posttranslational modification is found for instance in some coagulation factors (prothrombin, factor IX, etc.), in MGP, a protein implicated in tissue mineralization, and in osteocalcin, a bone-derived hormone affecting glucose metabolism. However, we still don’t know all the γ-carboxylated proteins and their functions.Recent findings in humans and rodents suggest that vitamin K and γ-carboxylation may be involved in the control of energy metabolism and the development of obesity and diabetes. Our current goal is to address γ-carboxylation function in vivo through the generation of tissue-specific knockout mice for the enzymes implicated in this process.We are also planning to characterize, in a non-bias proteomic approach, the “γ-carboxylome” (i.e. identifying all the GLA proteins produced in tissues were the γ-glutamyl carboxylase is expressed).

Mathieu Ferron est directeur de l’Unité de recherche en physiologie moléculaire de l’Institut de recherches cliniques de Montréal et titulaire de la Chaire de recherche du Canada en métabolisme osseux et énergétique. Il s’intéresse au rôle joué par la vitamine K dans le métabolisme énergétique et au rôle endocrinien du tissu osseux.

Les travaux de M. Ferron et de son équipe de recherche ont permis de mettre en évidence que le tissu osseux avait une fonction importante dans le métabolisme énergétique. Ultimement, les découvertes qui émergeront de ces études permettront de mieux comprendre les fonctions physiologiques de l’os et du pancréas, et pourraient conduire à de meilleures façons de traiter le diabète, l’obésité et l'ostéoporose.

Stagiaire postdoctoral et étudiant(e) de cycle supérieur – Laboratoire de physiologie intégrative et moléculaire

Nous recherchons des candidat(e)s au postdoctorat, au doctorat ou à la maitrise intéressés par la biologie cellulaire, la biochimie, la physiologie et le métabolisme énergétique.

Projets de recherche :

Notre laboratoire s’intéresse à la régulation du tissue osseux et du métabolisme énergétique par différents organes et types cellulaires, ainsi qu’aux interactions endocriniennes entre ces organes.  Nous faisons appel à des approches de biochimie, de protéomique et de biologie cellulaire et moléculaire, et prenons également avantage de souris knockout afin d’étudier la fonction des voies de signalisations impliquées in vivo. Plusieurs projets sont présentement en cours et disponible, pour plus de détail voir le microsite de l’unité de recherche.

Références :

Lacombe, J., Rishavy, M.A., Berkner, K.L., Ferron, M*. VKOR paralog VKORC1L1 supports vitamin K-dependent protein carboxylation in vivo. JCI Insight. 2018, 3(1): e96501.

Al Rifai, O., Chow, J., Lacombe, J., Julien, C., Faubert, D., Susan-Resiga, D., Essalmani, R., Creemers, J.W., Seidah, N.G., Ferron, M*. Proprotein convertase furin regulates osteocalcin and bone endocrine function. The Journal of Clinical Investigation. 2017, 127(11), 4104-4117.

Ferron, M.*, Lacombe, J., Germain, A., Oury, F. and Karsenty, G*. GGCX and VKORC1 inhibit osteocalcin endocrine functions. J Cell Biol. 2015, 208(6), 761-776.

Qualifications requise :

Être titulaire d’un baccalauréat et/ou d’une maitrise en biochimie ou biologie moléculaire (ou équivalent) et répondre au critère d’admissibilité aux programmes de Biologie Moléculaire ou de Biochimie de l’Université de Montréal, ou d’Experimental Medicine de l’Université McGill. Nous recherchons particulièrement des étudiant(e)s persévérants, passionnés par la science et souhaitant faire carrière en recherche. De plus, les candidats possédant de l’expérience de laboratoire et ayant maintenue une excellente moyenne pondérée cumulative sont fortement encouragés à appliquer. Les candidats pour le postdoc doivent avoir un PhD ou un doctorat en biochimie ou biologie moléculaire (ou équivalent)

Les personnes intéressés doivent envoyer une lettre de motivation, un C.V. complet, les relevés de notes universitaires et les coordonnées de deux personnes pouvant servir de références à Dr Mathieu Ferron : mathieu.ferron@ircm.qc.ca

Lacombe J., Al Rifai, O., Loter, L., Moran, T., Turcotte, A.F., Grenier-Larouche, T., Tchernof, A., Biertho, L., Carpentier, A.C., Prud’homme, D., Rabasa-Lhoret, R., Karsenty, G., Gagnon, C., Jiang, W., Ferron,M.* Measurement of bioactive osteocalcin in humans using a novel immunoassay reveals association with glucose metabolism and b-cell function. Am J Physiol Endocrinol Metab. 2020. In press.

Lacombe J., Ferron M.* VKORC1L1, An Enzyme Mediating the Effect of Vitamin K in Liver and Extrahepatic Tissues. Nutrients. 2018, 10, e970.

Carter, S., Miard, M., Caron, A., Sallé-Lefort, S., St-Pierre, P., Anhê, F.F., Lavoie-Charland, E., Blais-Lecours, P., Drolet, M.C., Lefebvre, J.S., Lacombe, J., Deshaies, Y., Couet, J., Laplante, M., Ferron, M., Bossé, Y., Marette, A., Richard, D., Marsolais, D., Picard, F. Loss of OcaB prevents age-induced fat accretion and insulin resistance by altering B-lymphocyte transition and promoting energy expenditure. Diabetes. 2018, 67, 1285-1296. 

Lacombe, J., Rishavy, M.A., Berkner, K.L., Ferron, M*. VKOR paralog VKORC1L1 supports vitamin K-dependent protein carboxylation in vivo. JCI Insight. 2018, 3, e96501.

Al Rifai, O., Chow, J., Lacombe, J., Julien, C., Faubert, D., Susan-Resiga, D., Essalmani, R., Creemers, J.W., Seidah, N.G., Ferron, M*. Proprotein convertase furin regulates osteocalcin and bone endocrine function. J Clin Invest. 2017, 127, 4104-4117

Boraschi-Diaz, I., Tauer, JT., Al Rifai, O., Guillemette, D., Lefebvre, G., Rauch, F., Ferron, M., Komarova SV. Metabolic phenotype in the mouse model of osteogenesis imperfecta. J Endocrinol. 2017, 234, 279-289.

Marulanda, J., Eimar, H., McKee, M.D., Berkvens, M., Nelea, V., Roman, H., Borras, T., Tamimi, F., Ferron, M. Murshed, M. Matrix Gla Protein Deficiency Impairs Nasal Septum Growth Causing Midface Hypoplasia. J Biol Chem. 2017, 292, 11400-11412.

Bonneau, J., Ferland, G., Karelis, A.D., Doucet, É., Faraj, M., Rabasa-Lhoret, R., Ferron M.* Association between osteocalcin gamma-carboxylation and insulin resistance in overweight and obese postmenopausal women. J of Diabetes Complications. 2017, 31, 1027-1034.

Mera, P., Laue, K., Ferron, M., Confavreux, C., Wei, J., Galan-Diez, M., Lacampagne, A., Mitchell, S.J., Mattison, J.A., Chen, Y., Bacchetta, J., Szulc, P., Kitsis, R.N., de Cabo, R., Friedman, R.A., Torsitano, C., McGraw, T.E., Puchowicz, M., Kurland, I., Karsenty G. Osteocalcin signaling in myofibers is necessary and sufficient for optimum adaptation to exercise. Cell Metab. 2016, 23, 1078-92.

Oropeza, D., Jouvet, N., Budry, L., Campbell, J.E., Bouyakdan, K., Lacombe, J., Perron, G., Bergeron, V., Neuman, J.C., Brar, H.K., Fenske, R.J., Meunier, C., Sczelecki, S., Kimple, M.E., Drucker, D.J., Screaton, R.A., Poitout, V., Ferron, M., Alquier, T., Estall, J.L. Phenotypic characterization of MIP-CreERT1Lphi mice with transgene-driven islet expression of human growth hormone. Diabetes. 2015, 64, 3798-807.

Ferron, M.#, Lacombe, J., Germain, A., Oury, F.  and Karsenty, G#. GGCX and VKORC1 inhibit osteocalcin endocrine functions. J Cell Biol. 2015, 208, 761-776.

#: co-corresponding authors and equal contribution from Ferron’s and Karsenty’s groups

Huesa, C., Zhu, D., Glover, J.D., Ferron, M., Karsenty, G., Milne, E.M., Milla, J.L., Ahmed, F.S., Farquharson, C., Morton, N.M. and MacRae, V.E. Deficiency of the bone mineralization inhibitor NPP1 protects mice against obesity and diabetes. Dis Model Mech. 2014, 7, 1341-50.

Bornstein, S., Brown, S.A., Le, P.T., Wang, X., DeMambro, V., Horowitz, M.C., MacDougald, O., Baron, R., Lotinun, S., Karsenty, G., Wei, W., Ferron, M., Kovacs, C.S., Clemmons, D., Wan, Y., Rosen, C.J. FGF-21 and skeletal remodeling during and after lactation in C57BL/6J mice. Endocrinology, 2014, 155, 3516-26.

Riddle, R.C., Frey, J.L., Tomlinson, R.E., Ferron, M., Li, Y., Digirolamo, D.J., Faugere, M.C., Hussain, M.A., Karsenty, G., Clemens, T.L. Tsc2 is a molecular checkpoint controlling osteoblast development and glucose homeostasis. Mol Cell Biol, 2014, 34, 1850-62.

Wei, J., Ferron, M., Clarke, C.J., Hannun, Y.A., Jiang, H.,  Blanner, W.S., Karsenty, G. Bone-specific insulin resistance disrupts whole-body glucose homeostasis via decreased osteocalcin activation. J Clin Invest. 2014, 124, 1781-93.

Nohara, K., Liu, S., Meyers, M.S., Waget, A., Ferron, M., Karsenty, G., Burcelin, R., Mauvais-Jarvis, F. Developmental androgen excess disrupts reproduction and energy homeostasis in adult male mice. J Endocrinol. 2013, 219, 259-68.

Lacombe, J., Karsenty, G., Ferron, M.* In vivo analysis of the contribution of bone resorption to the control of glucose metabolism in mice. Mol Metab. 2013,  2, 498-504.

Gillespie, J.R., Bush, J.R., Bell, G.I., Aubrey, L.A., Dupuis, H., Ferron, M., Kream, B., DiMattia, G., Patel, S., Woodgett, J.R., Karsenty, G., Hess, D.A., Beier, F. GSK-3 function in bone regulates skeletal development, whole body metabolism, and male life span. Endocrinology. 2013, 154, 3702-18.

Kajimura, D., Lee, H.W., Riley, K.J., Artega-Solis, E., Ferron, M., Zhou, B., Clarke, C.J., Hannun, Y.A., DePinho, R.A. Guo, E.X., Mann, J.J., Karsenty, G. Adiponectin regulates bone mass via opposite central and peripheral mechanisms through FoxO1. Cell Metab. 2013,  17, 901-15.

Oury, F., Ferron, M., Huizhen, W., Confavreux, C., Xu, L., Lacombe, J., Srinivas, P.,  Chamouni, A., Lugani, F., Lejeune, H., Kumar, T.R., Plotton, I., Karsenty, G. Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis. J Clin Invest. 2013, 123, 2421-33.

Nohara, K., Waraich, R., Liu, S., Ferron, M., Waget, A., Meyers, M., Karsenty, G., Burcelin, R., and Mauvais-Jarvis, F. Developmental androgen excess programs sympathetic tone and adipose tissue dysfunction and predisposes to a cardiometabolic syndrome in female mice. Am J Physiol Endocrinol Metab. 2013, 304, E1321-30.

Ferron, M. Settembre, C., Shimazu, J., Lacombe, J., Kato, S., Rawlings, D.J., Ballabio, A., Karsenty, G. A RANKL-PKCb-TFEB signaling cascade is necessary for lysosomal biogenesis in osteoclasts. Genes Dev. 2013, 27, 955-69.

Settembre, C., Zoncu, R., Medina, D.L., Vetrini, F., Erdin, S., Erdin, S.U., Huynh, T., Ferron, M., Karsenty, G., Vellard, M.C., Facchinetti, V., Sabatini, D., Ballabio, A. A lysosome-to-nucleus signaling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 2012, 31, 1095-108.

Kode, A., Mosialou, I., Silva, B.C., Joshi, S., Ferron, M., Rached, M.T., Kousteni, S. FoxO1 protein cooperates with ATF4 in osteoblasts to control glucose homeostasis. J Biol Chem. 2012, 287, 8757-68.

Ferron, M., McKee, M.D., Levine, R.L., Ducy, P., Karsenty, G. Intermittent injections of osteocalcin improve glucose metabolism and prevent type 2 diabetes in mice. Bone. 2012, 50, 568-75.

Ferron, M., Boudiffa, M., Arsenault, M., Rached, M., Pata, M., Giroux, S., Elfassihi, L., Kisseleva, M., Majerus, P.W., Rousseau, F., Vacher, J. Inositol polyphosphate 4-phosphatase B as a regulator of bone mass in mice and humans. Cell Metab. 2011, 14, 466-477.

Yoshikawa, Y., Kode, A., Xu, L., Mosialos. I, Silva, B., Ferron, M., Clemens, T.L., Economides, A.N., Kousteni, S. Genetic evidence points to an osteocalcin-independent influence of osteoblasts on energy metabolism. J Bone Miner Res. 2011, 26, 2012-25.

Kajimura, D., Hinoi, E., Ferron, M., Kode, A., Riley, K.J., Zhou, B., Guo, X.E., Karsenty, G. Genetic determination of the cellular basis of the sympathetic regulation of bone mass accrual. J Exp Med. 2011, 208, 841-51.

Oury, F., Sumara, G., Sumara, O., Ferron, M., Chang, H., Smith, C.E., Hermo, L., Suarez, S., Roth, B.L., Ducy, P., Karsenty, G. Endocrine regulation of male fertility by the skeleton. Cell. 2011, 144, 796-809.

Ferron, M., Wei, J., Yoshizawa, T., Del Fattore, A., DePinho, R.A., Teti, A., Ducy, P. Karsenty, G. Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell. 2010, 142, 296-308.

Ferron, M., Wei, J., Yoshizawa, T., Ducy, P. and Karsenty, G. An ELISA-Based method to quantify osteocalcin carboxylation in mice. Biochem Biophys Res Commun. 2010, 397, 691-696.

Yoshizawa, T., Hinoi, E., Jung, D.Y., Kajimura, D., Ferron, M., Seo, J., Graff, J.M., Kim, J.K., Karsenty, G. The transcription factor ATF4 regulates glucose metabolism in mice through its expression in osteoblasts. J Clin Invest. 2009, 119, 2807-17.

Ferron, M., Hinoi, E., Karsenty, G., Ducy, P. Osteocalcin differentially regulates b-cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc Natl Acad Sci. 2008, 105, 5266-70.

Lee, N.K., Sowa, H., Hinoi, E., Ferron, M., Ahn, J.D., Confavreux, C., Dacquin, R., Mee, P.J., McKee, M.D., Jung, D.Y., Zhang, Z., Kim, J.K., Mauvais-Jarvis, F., Ducy, P., Karsenty, G. Endocrine regulation of energy metabolism by the skeleton. Cell. 2007, 130, 456-469.

Ferron, M., Vacher, J. Characterization of the murine Inpp4b gene and identification of a novel isoform. Gene. 2006, 376, 152-61.

Ferron, M., Vacher, J. Targeted expression of Cre recombinase in macrophages and osteoclasts in transgenic mice. Genesis. 2005, 41, 138-45.

Chalhoub, N., Benachenhou, N., Rajapurohitam, V., Pata, M., Ferron, M., Frattini, A., Villa, A., Vacher, J. Grey-lethal mutation induces severe malignant autosomal recessive osteopetrosis in mouse and human. Nature Medicine. 2003, 9, 399-406.

2019-05       Boston-Ithaca Islet Club meeting, New York, NY, USA. “Development of a new method to measure human undercarboxylated osteocalcin levels in diabetes.”

2018-06       Novel Aspects of Bone Biology Keystone Symposia, Showbird, UT, USA. “The Endocrine Function of the Osteoblast”. Session chair.

2018-01       Bones & Teeth Gordon Research Conferences, Galveston, TX, USA. Title: “Proprotein Convertase Furin Is a Novel Pleiotropic Regulator of Bone Endocrine Functions”

2016-02       Bones & Teeth Gordon Research Conferences, Galveston, TX, USA. Title: “Novel Role of Vitamin K-Dependent Gamma-Carboxylation in Bone Remodeling”

2015-07       Molecular, Structural and Clinical Aspects of Vitamin K and Vitamin K Dependent Proteins, FASEB Summer Research Conference, Itasca, IL, USA. Title: “Role of -glutamyl carboxylase and vitamin K reductases in glucose metabolism and in bone remodeling”

2014-10       Novo Nordisk New England and Eastern Canada Diabetes and Obesity Biologics Science Forum, Joseph B Martin Conference Center at Harvard Medical School, Boston, MA. Title: “Identification of new bone-derived osteokines by proteomics”

2013-04       VII^ème Congrès de physiologie, de pharmacologie et de thérapeutique, Angers, France. Title: “γ-Glutamyl Carboxylase Regulates Whole Body Energy Metabolism Through Its Expression In Osteoblasts”