GGCX and VKORC1 inhibit osteocalcin endocrine functions.
Osteocalcin (OCN) is an osteoblast-derived hormone favoring glucose homeostasis, energy expenditure, male fertility, brain development, and cognition. Before being secreted by osteoblasts in the bone extracellular matrix, OCN is γ-carboxylated by the γ-carboxylase (GGCX) on three glutamic acid residues, a cellular process requiring reduction of vitamin K (VK) by a second enzyme, a reductase called VKORC1. Although circumstantial evidence suggests that γ-carboxylation may inhibit OCN endocrine functions, genetic evidence that it is the case is still lacking. Here we show using cell-specific gene inactivation models that γ-carboxylation of OCN by GGCX inhibits its endocrine function. We further show that VKORC1 is required for OCN γ-carboxylation in osteoblasts, whereas its paralogue, VKORC1L1, is dispensable for this function and cannot compensate for the absence of VKORC1 in osteoblasts. This study genetically and biochemically delineates the functions of the enzymes required for OCN modification and demonstrates that it is the uncarboxylated form of OCN that acts as a hormone.
Unité de recherche en physiologie intégrative et moléculaire, Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada Département de médecine, Département de biochimie et médecine moléculaire, and Programmes de biologie moléculaire, Université de Montréal, Montréal, Québec H3C 3J7, Canada Département de médecine, Département de biochimie et médecine moléculaire, and Programmes de biologie moléculaire, Université de Montréal, Montréal, Québec H3C 3J7, Canada Département de médecine, Département de biochimie et médecine moléculaire, and Programmes de biologie moléculaire, Université de Montréal, Montréal, Québec H3C 3J7, Canada Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec H3A 1A3, Canada mathieu.ferron@ircm.qc.ca gk2172@columbia.edu.
Mathieu
M
Ferron
Unité de recherche en physiologie intégrative et moléculaire, Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.
Julie
J
Lacombe
Unité de recherche en physiologie intégrative et moléculaire, Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada Département de médecine, Département de biochimie et médecine moléculaire, and Programmes de biologie moléculaire, Université de Montréal, Montréal, Québec H3C 3J7, Canada.
Amélie
A
Germain
Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
Franck
F
Oury
Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032 mathieu.ferron@ircm.qc.ca gk2172@columbia.edu.
Gérard
G
Karsenty
D000818:Animals; D019735:Carbon-Carbon Ligases / Q000502:physiology*; D002450:Cell Communication; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D005260:Female; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance; D007333:Insulin Resistance; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D008822:Mice, Transgenic; D009765:Obesity / Q000209:etiology / Q000378:metabolism; D010006:Osteoblasts; D015675:Osteocalcin / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D064417:Vitamin K Epoxide Reductases / Q000502:physiology*
D008565:Membrane Proteins; D015675:Osteocalcin; C000597964:VKORC1 protein, mouse; D064417:Vitamin K Epoxide Reductases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase; D005947:Glucose