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GGCX and VKORC1 inhibit osteocalcin endocrine functions
#MMPMID25753038
Ferron M
; Lacombe J
; Germain A
; Oury F
; Karsenty G
J Cell Biol
2015[Mar]; 208
(6
): 761-76
PMID25753038
show ga
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
?-carboxylated by the ?-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
?-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 ?-carboxylation of OCN by GGCX inhibits its endocrine function. We
further show that VKORC1 is required for OCN ?-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.
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