Osteocalcin (OCN) is an osteoblast-derived hormone that increases energy expenditure, insulin sensitivity, insulin secretion, and glucose tolerance. The cDNA sequence of OCN predicts that, like many other peptide hormones, OCN is first synthesized as a prohormone (pro-OCN). The importance of pro-OCN maturation in regulating OCN and the identity of the endopeptidase responsible for pro-OCN cleavage in osteoblasts are still unknown. Here, we show that the proprotein convertase furin is responsible for pro-OCN maturation in vitro and in vivo. Using pharmacological and genetic experiments, we also determined that furin-mediated pro-OCN cleavage occurred independently of its γ-carboxylation, a posttranslational modification that is known to hamper OCN endocrine action. However, because pro-OCN is not efficiently decarboxylated and activated during bone resorption, inactivation of furin in osteoblasts in mice resulted in decreased circulating levels of undercarboxylated OCN, impaired glucose tolerance, and reduced energy expenditure. Furthermore, we show that Furin deletion in osteoblasts reduced appetite, a function not modulated by OCN, thus suggesting that osteoblasts may secrete additional hormones that regulate different aspects of energy metabolism. Accordingly, the metabolic defects of the mice lacking furin in osteoblasts became more apparent under pair-feeding conditions. These findings identify furin as an important regulator of bone endocrine function.

中文翻译：

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前蛋白转化酶弗林蛋白酶调节骨钙素和骨内分泌功能

骨钙素（OCN）是一种成骨细胞源性激素，可增加能量消耗，胰岛素敏感性，胰岛素分泌和葡萄糖耐量。OCN的cDNA序列预测，与许多其他肽激素一样，OCN首先被合成为激素原（pro-OCN）。尚不成熟的前OCN调节OCN和负责成骨细胞中的前OCN裂解的内肽酶的身份仍然未知。在这里，我们显示前蛋白转化酶弗林蛋白酶在体外和体内负责促OCN的成熟。使用药理和遗传实验，我们还确定弗林蛋白酶介导的OCN裂解独立于其γ-羧基化而发生，γ-羧基化是一种已知会阻碍OCN内分泌作用的翻译后修饰。然而，由于pro-OCN在骨吸收过程中不能有效地脱羧和活化，因此小鼠成骨细胞中弗林蛋白酶的失活导致羧化OCN循环水平降低，葡萄糖耐量降低和能量消耗降低。此外，我们表明成骨细胞中弗林蛋白酶的缺失会降低食欲，这是不受OCN调节的功能，因此表明成骨细胞可能会分泌其他激素，这些激素调节能量代谢的各个方面。因此，在成对喂养的条件下，成骨细胞中缺乏弗林蛋白酶的小鼠的代谢缺陷变得更加明显。这些发现确定弗林蛋白酶是骨内分泌功能的重要调节剂。