JCI: Bones can also affect your metabolism and appetite | intensive reading of the literature
Originally published as JCI Bones can also affect your 50l rotovap metabolism and appetite | intensive reading of the literature Foreword Recent studies have shown that bone as an endocrine organ secretes at least three hormones fibroblast growth factor 23 (FGF23) apolipoprotein 2 (LCN2) and osteocalcin (OCN) Osteoblasts are cells that synthesize OCN a hormone involved in the regulation of glucose and energy metabolism among other functions On a normal diet Ocn-deficient mice (Ocn-/-) exhibit reduced glucose tolerance insulin sensitivity and circulating insulin levels as well as reduced energy expenditure and increased fat content Mechanistic studies in cell culture and mice have shown that OCN regulates glucose better by promoting insulin secretion in pancreatic beta cells promoting glucose uptake in muscle fibers and increasing energy expenditure Mouse experiments indicate that the function of OCN in beta cells and myofibers is mediated by group C 6 member A of the G protein-coupled receptor family (GPRC6A) This pathway appears to be preserved in humans because human OCN can bind to and activate human GPRC6A and mutations or genetic polymorphisms in human GPRC6A are associated with insulin resistance OCN is a small protein (46 amino acids in mice and 49 amino acids in humans) that is synthesized by osteoblasts and whose three glutamic acid residues (Glu) are gamma-carboxylated before being secreted γ-Carboxylation of OCN occurs in the endoplasmic reticulum and is mediated by γ-glutamyl carboxylase (GGCX) a process that requires reduced levels of vitamin K as an essential cofactor This post-transcriptional modification increases the affinity of OCN for hydroxyapatite a mineral component of the extracellular matrix (ECM) of bone cells Therefore most of the OCN secreted by osteoblasts are deposited in the ECM of bone matrix constituting a large number of non-collagen polypeptides Although both γ-carboxylated (Gla) and partially carboxylated OCN (ucOCN) can be detected in serum most in vivo and in vitro studies have shown that the endocrine function of OCN in humans and mice is performed by ucOCN Recent studies have nutsche filter dryer shown that by specifically inactivating Ggcx in osteoblasts circulating levels of ucOCN in mice can be increased and glucose tolerance can be improved Other studies have shown that osteoclasts are responsible for the partial decarboxylation and activation of OCN in bone ECM Taken together these findings suggest that inactivated γ-carboxylated OCN is synthesized by osteoblasts and deposited in the bone ECM and is activated by osteoclasts and released as ucOCN during bone resorption Like many other peptide hormones the sequence of Ocn cDNA suggests that it was first synthesized as a preprohormone consisting of a signal peptide a propeptide and a mature hormone Propeptides of such preprohormones such as prothrombin and cofactor IX are characterized by a signal recognized by gamma-glutamyl carboxylase the propeptide of which is gamma-carboxylated However the importance of γ-carboxylation of the propeptide and OCN secretion has not been studied in vivo In addition it is not clear whether the removal of OCN propeptide depends on the γ-carboxylation process OCN is unique among all known γ-carboxylated proteins because it can be efficiently γ-carboxylated in the absence of the propeptide Finally and most importantly who are the endopeptidases that process OCN prohormones (pro-OCN) and the importance of OCN in bone endocrine function is unclear Therefore we searched for pro-OCN converting enzymes For this purpose we focused on proprotein convertases (PCs) PCs are a class of serine proteases that target specific motifs commonly found in prehormonal sequences consisting of basic residues such as arginine or lysine These enzymes act in the secretory pathway or outside the cell to cleave other proteins activate or inactivate them and then participate in the regulation of many biological processes
