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GGCX and VKORC1 inhibit osteocalcin endocrine functions
Mathieu Ferron1, Julie Lacombe2, Amélie Germain3
1Unité 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.
The uncarboxylated form of osteocalcin (OCN) acts as a hormone, regulating glucose and energy. Vitamin K-dependent gamma-carboxylation by GGCX inhibits OCN
Area of Science:
- Endocrinology
- Bone Biology
- Metabolism
Background:
- Osteocalcin (OCN) is an osteoblast-derived hormone influencing glucose homeostasis, energy expenditure, and cognitive functions.
- OCN undergoes gamma-carboxylation by gamma-carboxylase (GGCX), a process dependent on vitamin K (VK) and VKORC1.
- Previous evidence suggested gamma-carboxylation might inhibit OCN's endocrine roles, but lacked genetic validation.
Purpose of the Study:
- To genetically investigate the role of OCN gamma-carboxylation in its endocrine function.
- To determine the specific roles of VKORC1 and VKORC1L1 in osteoblast OCN modification.
- To elucidate the hormonal activity of OCN forms.
Main Methods:
- Cell-specific gene inactivation models in mice.
- Biochemical assays to assess OCN modification.
- Genetic analysis of VKORC1 and VKORC1L1 function in osteoblasts.
Main Results:
- Gamma-carboxylation of OCN by GGCX was shown to inhibit its endocrine function.
- VKORC1 is essential for OCN gamma-carboxylation in osteoblasts.
- VKORC1L1 cannot compensate for VKORC1 deficiency in osteoblast OCN carboxylation.
Conclusions:
- The uncarboxylated form of OCN is the active hormone.
- VKORC1 is the critical enzyme for OCN gamma-carboxylation in osteoblasts.
- This study genetically confirms the inhibitory effect of OCN gamma-carboxylation on its hormonal activity.
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