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Osteoclast Derivation from Mouse Bone Marrow
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Proprotein convertase furin regulates osteocalcin and bone endocrine function.

Omar Al Rifai1,2, Jacqueline Chow1, Julie Lacombe1

  • 1Integrative and Molecular Physiology Research Unit, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada.

The Journal of Clinical Investigation
|October 4, 2017
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Furin is essential for processing osteocalcin (OCN), a bone hormone regulating metabolism. Inactivation of furin in osteoblasts impairs glucose tolerance and energy expenditure, revealing furin's critical role in bone endocrine function.

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Area of Science:

  • Endocrinology
  • Bone Biology
  • Metabolism

Background:

  • Osteocalcin (OCN) is a bone-derived hormone influencing energy metabolism.
  • OCN is synthesized as a prohormone (pro-OCN), but its maturation process and the responsible enzyme are unknown.
  • The role of pro-OCN maturation in OCN's endocrine functions requires elucidation.

Purpose of the Study:

  • To identify the endopeptidase responsible for pro-OCN cleavage in osteoblasts.
  • To investigate the role of furin-mediated pro-OCN maturation in metabolic regulation.
  • To determine the impact of impaired pro-OCN processing on glucose tolerance and energy expenditure.

Main Methods:

  • In vitro and in vivo experiments using pharmacological and genetic approaches.
  • Assessment of pro-OCN cleavage and OCN activation.
  • Evaluation of glucose tolerance, energy expenditure, and appetite in mice with osteoblast-specific furin deletion.

Main Results:

  • The proprotein convertase furin was identified as the enzyme responsible for pro-OCN maturation.
  • Furin-mediated cleavage of pro-OCN occurs independently of its γ-carboxylation.
  • Inactivation of furin in osteoblasts led to decreased circulating undercarboxylated OCN, impaired glucose tolerance, and reduced energy expenditure.
  • Furin deletion in osteoblasts also reduced appetite, suggesting osteoblast secretion of other metabolic regulators.

Conclusions:

  • Furin is a key regulator of pro-OCN maturation and bone endocrine function.
  • Furin-dependent OCN processing is crucial for maintaining glucose homeostasis and energy expenditure.
  • Osteoblasts may secrete additional hormones involved in energy metabolism, independent of OCN.