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Medecine Sciences : M/S Jan 2018The maintenance of our physiological functions and their adaptive response to environmental changes depend on precise crosstalk between organs. Recent advances in mouse... (Review)
Review
The maintenance of our physiological functions and their adaptive response to environmental changes depend on precise crosstalk between organs. Recent advances in mouse genetics have helped demonstrate that this holistic view of physiology extends to the skeletal system, where many unexpected signaling axes are found to play essential roles affecting numerous organs. After being long regarded as a static tissue, functioning merely as a structural support system, the skeleton has seen its image evolve into a much more complex picture. The skeleton reveals itself as a key endocrine organ for the homeostasis of our body, both by its central position in our body, but also by the large number of physiological functions it influences. In this review, we discuss the multiple endocrine roles of osteocalcin, an osteoclast-derived molecule (Ocn), where its functional importance has steadily increased over the last 15 years.
Topics: Animals; Bone and Bones; Endocrine System; Energy Metabolism; Homeostasis; Humans; Osteocalcin; Osteoclasts
PubMed: 29384097
DOI: 10.1051/medsci/20183401014 -
Journal of Cellular Biochemistry Mar 1995Osteocalcin is a skeletal member of the family of extracellular mineral binding Gla protein. Osteocalcin is synthesized only by the osteoblast and it is secreted into... (Review)
Review
Osteocalcin is a skeletal member of the family of extracellular mineral binding Gla protein. Osteocalcin is synthesized only by the osteoblast and it is secreted into the bone matrix at the time of bone mineralization. The mineral binding properties of osteocalcin as well as its spatial and temporal pattern of expression suggest that it plays a role during bone mineralization, however until now its biological function is unclear. To understand osteocalcin function during skeletogenesis we mutated the two osteocalcin genes by homologous recombination in embryonic stem (ES) cells. Eight targeted clones were identified by Southern analysis using external probes. One of these clones contributed to the germ line of mouse chimera. Interbreeding of heterozygotes is currently in progress. Mutant mice will be useful to understand osteocalcin function in vivo.
Topics: Animals; Gene Expression Regulation, Developmental; Mice; Multigene Family; Osteocalcin
PubMed: 7768973
DOI: 10.1002/jcb.240570302 -
Endocrine Regulations Apr 2011Osteocalcin (OC) is a small, acidic extracellular protein synthesized by osteoblasts during bone formation. 3 residues of gamma-carboxy glutamic acid, formed in a... (Review)
Review
Osteocalcin (OC) is a small, acidic extracellular protein synthesized by osteoblasts during bone formation. 3 residues of gamma-carboxy glutamic acid, formed in a vitamin K dependent process, enable highly specific binding to ionic or bone mineral calcium. Some OC is released to circulation (pOC) and can serve as a biomarker of bone turnover. A series of experiments indicated that OC is stress-responsive in ways that vary with the type of stressor. Those in which the HPA axis predominates slowly decrease OC synthesis and secretion while sympathetic neural activation rapidly increases pOC. The advent of an OC null mutant mouse (KO) led to discovery of several functions for the protein outside the skeleton, most notably in regulation of energy metabolism. The KO mouse also exhibits numerous behavioral traits that are characteristic of sensory impairment. The discovery of OC protein in sensory ganglia stimulated further investigation of the interaction of sensory responses and both OC gene expression and OC protein in trigeminal and dorsal root ganglia. A recently discovered G-coupled protein receptor has been suggested as a potential OC receptor in combination with calcium ions. Because of the importance of ionic calcium to signal transduction in the nervous system, the presence of this unique calcium binding protein in neurons led to the hypothesis that OC functions as a neuropeptide. Implications of this potential new function are discussed.
Topics: Animals; Bone and Bones; Calcium; Ganglia, Spinal; Mice; Mice, Knockout; Neuropeptides; Osteocalcin; Physical Conditioning, Animal; Rats; Receptors, G-Protein-Coupled; Signal Transduction; Stress, Physiological; Stress, Psychological
PubMed: 21615194
DOI: 10.4149/endo_2011_02_99 -
Casopis Lekaru Ceskych Dec 1990Osteocalcin, non-collagenous vitamin K dependent bone protein is as a biochemical indicator of osteoblastic activity and metabolic turnover in bone, valuable in the... (Review)
Review
Osteocalcin, non-collagenous vitamin K dependent bone protein is as a biochemical indicator of osteoblastic activity and metabolic turnover in bone, valuable in the diagnosis of several diseases and in investigations of the dynamics of osseous changes (processes) during treatment of osteopathies. Elevated osteocalcin levels are normal in childhood and adolescence. In the diurnal rhythm the peak is recorded in the early hours. Pathologically elevated values are associated with primary hyperparathyroidism, Paget's disease, chronic renal failure, acromegaly and some malignities. A rise in women during the early postmenopausal period signalizes an enhanced metabolic turnover of bone in those women who are candidates of postmenopausal osteoporosis. Low levels are as a rule recorded in advanced age, in nanism, hypoparathyroidism, type 1 diabetes, rheumatoid arthritis, vitamin D deficiency, vitamin K deficiency, hypercorticalism and glucocorticoid treatment.
Topics: Animals; Humans; Osteocalcin
PubMed: 2272072
DOI: No ID Found -
Advances in Biological Regulation Dec 2020Bone provides skeletal support and functions as an endocrine organ by producing osteocalcin, whose uncarboxylated form (GluOC) increases the metabolism of glucose and... (Review)
Review
Bone provides skeletal support and functions as an endocrine organ by producing osteocalcin, whose uncarboxylated form (GluOC) increases the metabolism of glucose and lipid by activating its putative G protein-coupled receptor (family C group 6 subtype A). Low doses (≤10 ng/ml) of GluOC induce the expression of adiponectin, adipose triglyceride lipase and peroxisome proliferator-activated receptor γ, and promote active phosphorylation of lipolytic enzymes such as perilipin and hormone-sensitive lipase via the cAMP-PKA-Src-Rap1-ERK-CREB signaling axis in 3T3-L1 adipocytes. Administration of high-dose (≥20 ng/ml) GluOC induces programmed necrosis (necroptosis) through a juxtacrine mechanism triggered by the binding of Fas ligand, whose expression is induced by forkhead box O1, to Fas that is expressed in adjacent adipocytes. Furthermore, expression of adiponectin and adipose triglyceride lipase in adipocytes is triggered in the same manner as following low-dose GluOC stimulation; these effects protect mice from diet-induced accumulation of triglycerides in hepatocytes and consequent liver injury through the upregulation of nuclear translocation of nuclear factor-E2-related factor-2, expression of antioxidant enzymes, and inhibition of the c-Jun N-terminal kinase pathway. Evaluation of these molecular mechanisms leads us to consider that GluOC might have potential as a treatment for lipid metabolism disorders. Indeed, there have been many reports demonstrating the negative correlation between serum osteocalcin levels and obesity or non-alcoholic fatty liver disease, a common risk factor for which is dyslipidemia in humans. The present review summarizes the effects of GluOC on lipid metabolism as well as its possible therapeutic application for metabolic diseases including obesity and dyslipidemia.
Topics: Adiponectin; Adipose Tissue; Animals; Humans; Lipid Metabolism; Liver; Mice; Necroptosis; Osteocalcin; Signal Transduction
PubMed: 32992234
DOI: 10.1016/j.jbior.2020.100752 -
Reviews in Endocrine & Metabolic... Jun 2015A recent unexpected development of bone biology is that bone is an endocrine organ contributing to the regulation of a number of physiological processes. One of the... (Review)
Review
A recent unexpected development of bone biology is that bone is an endocrine organ contributing to the regulation of a number of physiological processes. One of the functions regulated by bone through osteocalcin, an osteoblast specific hormone, is glucose homeostasis. In this overview, we explain the rationale why we hypothesized that there should be a coordinated endocrine regulation between bone mass and energy metabolism. We then review the experiments that identified the endocrine function of osteocalcin and the cell biology events that allow osteocalcin to become a hormone. We also demonstrate the importance of this regulation to understand whole-body glucose homeostasis in the physiological state and in pathological conditions. Lastly we discuss the epidemiological and genetic evidence demonstrating that this function of osteocalcin is conserved in humans.
Topics: Animals; Bone and Bones; Energy Metabolism; Humans; Insulin; Insulin Secretion; Osteoblasts; Osteocalcin; Protein Processing, Post-Translational; Receptors, G-Protein-Coupled
PubMed: 25577163
DOI: 10.1007/s11154-014-9307-7 -
Current Osteoporosis Reports Jun 2015A recent unexpected development of bone biology is that bone is an endocrine organ regulating a growing number of physiological processes. One of the functions regulated... (Review)
Review
A recent unexpected development of bone biology is that bone is an endocrine organ regulating a growing number of physiological processes. One of the functions regulated by bone through the hormone osteocalcin is glucose homeostasis. In this overview, we will explain why we hypothesized that bone mass and energy metabolism should be subjected to a coordinated endocrine regulation. We will then review the experiments that revealed the endocrine function of osteocalcin and the cell biology events that allow osteocalcin to become a hormone. We will also illustrate the importance of this regulation to understand whole-body glucose homeostasis in the physiological state and in pathological conditions. Lastly, we will mention epidemiological and genetic evidence demonstrating that this function of osteocalcin is conserved in humans.
Topics: Animals; Bone Density; Disease Models, Animal; Endocrine System; Energy Metabolism; Glucose; Homeostasis; Humans; Insulin; Mice; Mice, Knockout; Osteocalcin
PubMed: 25809656
DOI: 10.1007/s11914-015-0267-y -
Journal of Cellular Physiology Jun 2013Osteocalcin (OC) is a non-collagenous, vitamin K-dependent protein secreted in the late stage of osteoblasts differentiation. The presence of the three residues of... (Review)
Review
Osteocalcin (OC) is a non-collagenous, vitamin K-dependent protein secreted in the late stage of osteoblasts differentiation. The presence of the three residues of γ-carbossiglutamatic acid, specific of the active form of OC protein, allows the protein to bind calcium and consequently hydroxyapatite. The osteoblastic OC protein is encoded by the bone γ-carbossiglutamate gene whose transcription is principally regulated by the Runx2/Cbfa1 regulatory element and stimulated by vitamin D(3) through a steroid-responsive enhancer sequence. Even if data obtained in literature are controversial, the dual role of OC in bone can be presumed as follows: firstly, OC acts as a regulator of bone mineralization; secondly, OC regulates osteoblast and osteoclast activity. Recently the metabolic activity of OC, restricted to the un-carboxylated form has been demonstrated in osteoblast-specific knockout mice. This effect is mediated by the regulation of pancreatic β-cell proliferation and insulin secretion and adiponectin production by adipose tissue and leads to the regulation of glucose metabolism and fat mass. Nevertheless, clinical human studies only demonstrated the correlation between OC levels and factors related to energy metabolism. Thus further investigations in humans are required to demonstrate the role of OC in the regulation of human energy metabolism. Moreover, it is presumable that OC also acts on blood vessels by inducing angiogenesis and pathological mineralization. This review highlights the recent studies concerning skeletal and extra-skeletal effects of OC.
Topics: Adiposity; Animals; Bone Remodeling; Bone and Bones; Calcinosis; Energy Metabolism; Gene Expression Regulation; Humans; Neovascularization, Physiologic; Osteoblasts; Osteocalcin; Osteocytes; Signal Transduction
PubMed: 23139068
DOI: 10.1002/jcp.24278 -
Endocrinologia Y Nutricion : Organo de... May 2013Research in animal models has demonstrated the role of osteocalcin, a bone formation marker, in regulation of energy metabolism. Those studies have led to a new concept... (Review)
Review
Research in animal models has demonstrated the role of osteocalcin, a bone formation marker, in regulation of energy metabolism. Those studies have led to a new concept of the bone acting as an endocrine organ by secreting osteocalcin, which acts by increasing insulin secretion, lowering plasma glucose, and increasing insulin sensitivity and energy expenditure. Results in humans have been conflicting. On the other hand, antiresorptive drugs used against osteoporosis decrease osteocalcin levels, while anabolic drugs increase osteocalcin levels. However, the effects of these therapies on energy metabolism have not been investigated.
Topics: Animals; Bone and Bones; Energy Metabolism; Homeostasis; Humans; Osteocalcin
PubMed: 23218238
DOI: 10.1016/j.endonu.2012.06.008 -
Biochimica Et Biophysica Acta. General... Mar 2021The carboxylation status of Osteocalcin (Ocn) not only influences formation and structure in bones but also has important endocrine functions affecting energy metabolism... (Review)
Review
BACKGROUND
The carboxylation status of Osteocalcin (Ocn) not only influences formation and structure in bones but also has important endocrine functions affecting energy metabolism and expenditure. In this study, the role of γ-carboxylation of the glutamate residues in the structure-dynamics-function relationship in Ocn is investigated.
METHODS
Three forms of Ocn, differentially carboxylated at the Glu-17, 21 and 24 residues, along with a mutated form of Ocn carrying Glu/Ala mutations, are modeled and simulated using molecular dynamics (MD) simulation in the presence of calcium ions.
RESULTS
Characterization of the global conformational dynamics of Ocn, described in terms of the orientational variations within its 3-helical domain, highlights large structural variations in the non-carboxylated osteocalcin (nOcn). The bi-carboxylated Ocn (bOcn) and tri-carboxylated (tOcn) species, in contrast, display relatively rigid tertiary structures, with the dynamics of most regions strongly correlated. Radial distribution functions calculated for both bOcn and tOcn show long-range ordering of the calcium ion distribution around the carboxylated glutamate (γGlu) residues, likely playing an important role in promoting stability of these Ocns. Additionally, the same calcium ions are observed to coordinate with neighboring γGlu, better shielding their negative charges and in turn stabilizing these systems more than do the singly coordinating calcium ions observed in the case of nOcn. bOcn is also found to exhibit a more helical C-terminal structure, that has been shown to activate its cellular receptor GPRC6A, highlighting the allosteric role of Ocn carboxylation in modulating the stability and binding potential of the active C-terminal.
CONCLUSIONS
The carboxylation status of Ocn as well and its calcium coordination appear to have a direct influence on Ocn structure and dynamics, possibly leading to the known differences in Ocn biological function.
GENERAL SIGNIFICANCE
Modification of Ocn sequence or its carboxylation state may provide the blueprint for developing high-affinity peptides targeting its cellular receptor GPRC6A, with therapeutic potential for treatment of metabolic disorders.
Topics: Amino Acid Sequence; Animals; Calcium; Carboxylic Acids; Glutamic Acid; Humans; Molecular Dynamics Simulation; Osteocalcin; Protein Conformation; Protein Stability
PubMed: 33340588
DOI: 10.1016/j.bbagen.2020.129809