GGCX and VKORC1 inhibit osteocalcin endocrine functions.
GGCX and VKORC1 inhibit osteocalcin endocrine functions.
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DOI：
10.1083/jcb.201409111
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发表时间：
2015-03-16
期刊：
影响因子：
--
通讯作者：
Karsenty G
中科院分区：
文献类型：
--
作者：
Ferron M;Lacombe J;Germain A;Oury F;Karsenty G
细胞特异性基因失活实验描绘了骨钙素修饰所需的酶的功能，并证明了它是作为激素的未羧化形式。骨钙素(OCN)是一种成骨细胞衍生的激素，可促进葡萄糖稳态、能量消耗、男性生育、脑发育和认知。在被骨细胞外基质中的成骨细胞分泌之前，OCN被三个谷氨酸残基上的γ-Carboxylase(GGCx)进行γ-Carboxylated，这是一个需要第二种酶还原维生素K(VK)的细胞过程，这种还原酶称为VKORC1.虽然间接证据表明γ-羧化可能抑制OCN的内分泌功能，但遗传证据仍然缺乏这种情况。在这里，我们使用细胞特异的基因失活模型表明，GGCX对OCN的γ羧化抑制了其内分泌功能。我们进一步证明VKORC1OCN是成骨细胞γ-羧化所必需的，而它的类似物VKORC1L1对于这一功能是不必要的，不能弥补成骨细胞中VKORC1.这项研究从遗传和生物化学的角度描述了OCN修饰所需的酶的功能，并证明了OCN的未羧化形式起到了激素的作用。
Cell-specific gene inactivation experiments delineate the functions of the enzymes required for osteocalcin modification and demonstrate that it is its uncarboxylated form that acts as a hormone. 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.
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影响因子：
64.5
作者：
Ferron M;Wei J;Yoshizawa T;Del Fattore A;DePinho RA;Teti A;Ducy P;Karsenty G
通讯作者：
Karsenty G
DOI：
10.1073/pnas.89.14.6242
发表时间：
1992-07-15
影响因子：
11.1
作者：
BERKNER, KL;HARBECK, M;SUTTIE, JW
通讯作者：
SUTTIE, JW
影响因子：
2.5
作者：
CHAPPARD, D;PALLE, S;RIFFAT, G
通讯作者：
RIFFAT, G
影响因子：
20.3
作者：
Czogalla, Katrin J.;Biswas, Arijit;Oldenburg, Johannes
通讯作者：
Oldenburg, Johannes
影响因子：
1.9
作者：
Abseyi N;Şıklar Z;Berberoğlu M;Hacıhamdioğlu B;Savaş Erdeve Ş;Öçal G
通讯作者：
Öçal G