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J Clin Invest. 2017 Nov 1;127(11):4104-4117. doi: 10.1172/JCI93437. Epub 2017 Oct 3.

Proprotein convertase furin regulates osteocalcin and bone endocrine function.

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Integrative and Molecular Physiology Research Unit, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada.
Molecular Biology Programs of the Faculty of Medicine, Université de Montréal, Québec, Canada.
Proteomics Discovery Platform and.
Biochemical Neuroendocrinology Research Unit, IRCM, Québec, Canada.
Department of Human Genetics, KU Leuven, Leuven, Belgium.
Department of Medicine, Université de Montréal, Québec, Canada.
Division of Experimental Medicine, McGill University, Montréal, Québec, Canada.


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.

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