GGCX and VKORC1 inhibit osteocalcin endocrine functions
نویسندگان
چکیده
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.
منابع مشابه
Gamma-carboxylation regulates osteocalcin function
The only well described function of vitamin K (VK) is to serve as a co-factor for the γ-carboxylation of particular proteins to convert specific glutamic acid (Glu) residues to γ-carboxyglutamic acid (Gla) residues. This process involves two enzymes, γ-glutamyl carboxylase (γ-carboxylase or GGCX) and vitamin K epoxide reductase (VKORC1), which together constitute the vitamin K cycle [1]. Physio...
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عنوان ژورنال:
دوره 208 شماره
صفحات -
تاریخ انتشار 2015