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Nature Reviews. Endocrinology Nov 2019Osteoblasts are specialized mesenchymal cells that synthesize bone matrix and coordinate the mineralization of the skeleton. These cells work in harmony with... (Review)
Review
Osteoblasts are specialized mesenchymal cells that synthesize bone matrix and coordinate the mineralization of the skeleton. These cells work in harmony with osteoclasts, which resorb bone, in a continuous cycle that occurs throughout life. The unique function of osteoblasts requires substantial amounts of energy production, particularly during states of new bone formation and remodelling. Over the last 15 years, studies have shown that osteoblasts secrete endocrine factors that integrate the metabolic requirements of bone formation with global energy balance through the regulation of insulin production, feeding behaviour and adipose tissue metabolism. In this article, we summarize the current understanding of three osteoblast-derived metabolic hormones (osteocalcin, lipocalin and sclerostin) and the clinical evidence that suggests the relevance of these pathways in humans, while also discussing the necessity of specific energy substrates (glucose, fatty acids and amino acids) to fuel bone formation and promote osteoblast differentiation.
Topics: Adaptor Proteins, Signal Transducing; Animals; Bone Remodeling; Energy Metabolism; Homeostasis; Humans; Lipocalins; Osteoblasts; Osteocalcin; Osteogenesis
PubMed: 31462768
DOI: 10.1038/s41574-019-0246-y -
Nutrients Jun 2020Vitamin K is essential for blood coagulation and plays an important role in extrahepatic metabolism, such as in bone and blood vessels, and in energy metabolism. This... (Review)
Review
Vitamin K is essential for blood coagulation and plays an important role in extrahepatic metabolism, such as in bone and blood vessels, and in energy metabolism. This review discusses the assessment of vitamin K sufficiency and the role of vitamin K in bone health. To elucidate the exact role of vitamin K in other organs, accurate tools for assessing vitamin K deficiency or insufficiency are crucial. Undercarboxylated vitamin K-dependent protein levels can be measured to evaluate tissue-specific vitamin K deficiency/insufficiency. Vitamin K has genomic action through steroid and xenobiotic receptor (SXR); however, the importance of this action requires further study. Recent studies have revealed that the bone-specific, vitamin K-dependent protein osteocalcin has a close relationship with energy metabolism through insulin sensitivity. Among the organs that produce vitamin K-dependent proteins, bone has attracted the most attention, as vitamin K deficiency has been consistently associated with bone fractures. Although vitamin K treatment addresses vitamin K deficiency and is believed to promote bone health, the corresponding findings on fracture risk reduction are conflicting. We also discuss the similarity of other vitamin supplementations on fracture risk. Future clinical studies are needed to further elucidate the effect of vitamin K on fracture risk.
Topics: Adult; Aged; Aged, 80 and over; Bone Density; Bone and Bones; Female; Fractures, Bone; Humans; Male; Middle Aged; Osteocalcin; Vitamin K; Vitamin K Deficiency; Young Adult
PubMed: 32605143
DOI: 10.3390/nu12071909 -
International Journal of Molecular... Oct 2020Osteocalcin (Ocn), which is specifically produced by osteoblasts, and is the most abundant non-collagenous protein in bone, was demonstrated to inhibit bone formation... (Review)
Review
Osteocalcin (Ocn), which is specifically produced by osteoblasts, and is the most abundant non-collagenous protein in bone, was demonstrated to inhibit bone formation and function as a hormone, which regulates glucose metabolism in the pancreas, testosterone synthesis in the testis, and muscle mass, based on the phenotype of Ocn mice by Karsenty's group. Recently, Ocn mice were newly generated by two groups independently. Bone strength is determined by bone quantity and quality. The new Ocn mice revealed that Ocn is not involved in the regulation of bone formation and bone quantity, but that Ocn regulates bone quality by aligning biological apatite (BAp) parallel to the collagen fibrils. Moreover, glucose metabolism, testosterone synthesis and spermatogenesis, and muscle mass were normal in the new Ocn mice. Thus, the function of Ocn is the adjustment of growth orientation of BAp parallel to the collagen fibrils, which is important for bone strength to the loading direction of the long bone. However, Ocn does not play a role as a hormone in the pancreas, testis, and muscle. Clinically, serum Ocn is a marker for bone formation, and exercise increases bone formation and improves glucose metabolism, making a connection between Ocn and glucose metabolism.
Topics: Animals; Biomarkers; Bone and Bones; Exercise; Gene Expression Regulation; Glucose; Humans; Male; Mechanical Phenomena; Muscles; Organ Specificity; Osteocalcin; Osteogenesis; Pancreas; Signal Transduction; Testis
PubMed: 33053789
DOI: 10.3390/ijms21207513 -
FEBS Letters Mar 2022Bone biology has long been driven by the question as to what molecules affect cell differentiation or the functions of bone. Exploring this issue has been an... (Review)
Review
Bone biology has long been driven by the question as to what molecules affect cell differentiation or the functions of bone. Exploring this issue has been an extraordinarily powerful way to improve our knowledge of bone development and physiology. More recently, a second question has emerged: does bone have other functions besides making bone? Addressing this conundrum revealed that the bone-derived hormone osteocalcin affects a surprisingly large number of organs and physiological processes, including acute stress response. This review will focus on this emerging aspect of bone biology taking osteocalcin as a case study and will show how classical and endocrine functions of bone help to define a new functional identity for this tissue.
Topics: Bone Development; Bone and Bones; Hormones; Osteocalcin
PubMed: 34913486
DOI: 10.1002/1873-3468.14259 -
Annual Review of Nutrition Aug 2023Together, loss- and gain-of-function experiments have identified the bone-derived secreted molecule osteocalcin as a hormone with a broad reach in rodents and primates.... (Review)
Review
Together, loss- and gain-of-function experiments have identified the bone-derived secreted molecule osteocalcin as a hormone with a broad reach in rodents and primates. Following its binding to one of three receptors, osteocalcin exerts a profound influence on various aspects of energy metabolism as well as steroidogenesis, neurotransmitter biosynthesis and thereby male fertility, electrolyte homeostasis, cognition, the acute stress response, and exercise capacity. Although this review focuses mostly on the regulation of energy metabolism by osteocalcin, it also touches on its other functions. Lastly, it proposes what could be a common theme between the functions of osteocalcin and between these functions and the structural functions of bone.
Topics: Animals; Male; Biological Transport; Cognition; Energy Metabolism; Osteocalcin; Stress Disorders, Traumatic, Acute; Humans
PubMed: 37603430
DOI: 10.1146/annurev-nutr-061121-091348 -
Frontiers in Endocrinology 2021In addition to its structural role, the skeleton serves as an endocrine organ that controls mineral metabolism and energy homeostasis. Three major cell types in bone -... (Review)
Review
In addition to its structural role, the skeleton serves as an endocrine organ that controls mineral metabolism and energy homeostasis. Three major cell types in bone - osteoblasts, osteoclasts, and osteocytes - dynamically form and maintain bone and secrete factors with systemic activity. Osteocalcin, an osteoblast-derived factor initially described as a matrix protein that regulates bone mineralization, has been suggested to be an osteoblast-derived endocrine hormone that regulates multiple target organs including pancreas, liver, muscle, adipose, testes, and the central and peripheral nervous system. Sclerostin is predominantly produced by osteocytes, and is best known as a paracrine-acting regulator of WNT signaling and activity of osteoblasts and osteoclasts on bone surfaces. In addition to this important paracrine role for sclerostin within bone, sclerostin protein has been noted to act at a distance to regulate adipocytes, energy homeostasis, and mineral metabolism in the kidney. In this article, we aim to bring together evidence supporting an endocrine function for sclerostin and osteocalcin, and discuss recent controversies regarding the proposed role of osteocalcin outside of bone. We summarize the current state of knowledge on animal models and human physiology related to the multiple functions of these bone-derived factors. Finally, we highlight areas in which future research is expected to yield additional insights into the biology of osteocalcin and sclerostin.
Topics: Adaptor Proteins, Signal Transducing; Animals; Bone and Bones; Endocrine System; Homeostasis; Hormones; Humans; Osteocalcin
PubMed: 33776907
DOI: 10.3389/fendo.2021.584147 -
The Journal of Clinical Investigation Feb 2022Through their ability to regulate gene expression in most organs, glucocorticoid (GC) hormones influence numerous physiological processes and are therefore key...
Through their ability to regulate gene expression in most organs, glucocorticoid (GC) hormones influence numerous physiological processes and are therefore key regulators of organismal homeostasis. In bone, GC hormones inhibit expression of the hormone Osteocalcin for poorly understood reasons. Here, we show that in a classical endocrine feedback loop, osteocalcin in return enhanced the biosynthesis of GC as well as mineralocorticoid hormones (adrenal steroidogenesis) in rodents and primates. Conversely, inactivation of osteocalcin signaling in adrenal glands significantly impaired adrenal growth and steroidogenesis in mice. Embryo-made osteocalcin was necessary for normal Sf1 expression in fetal adrenal cells and adrenal cell steroidogenic differentiation and therefore determined the number of steroidogenic cells present in the adrenal glands of adult animals. Embryonic, not postnatal, osteocalcin also governed adrenal growth, adrenal steroidogenesis, blood pressure, electrolyte equilibrium, and the rise in circulating corticosterone levels during the acute stress response in adult offspring. This osteocalcin-dependent regulation of adrenal development and steroidogenesis occurred even in the absence of a functional hypothalamus/pituitary/adrenal axis and explains why osteocalcin administration during pregnancy promoted adrenal growth and steroidogenesis and improved the survival of adrenocorticotropic hormone signaling-deficient animals. This study reveals that a bone-derived embryonic hormone influences lifelong adrenal functions and organismal homeostasis in the mouse.
Topics: Adrenal Glands; Animals; Female; Glucocorticoids; Homeostasis; Hypothalamo-Hypophyseal System; Macaca mulatta; Mice; Mice, Knockout; Osteocalcin; Pituitary-Adrenal System; Signal Transduction
PubMed: 34905510
DOI: 10.1172/JCI153752 -
Molecular Metabolism Jul 2021The bone-derived protein osteocalcin (OC), in its undercarboxylated (ucOC) form, has a beneficial effect on energy metabolism and may be a future therapeutic target for... (Review)
Review
BACKGROUND
The bone-derived protein osteocalcin (OC), in its undercarboxylated (ucOC) form, has a beneficial effect on energy metabolism and may be a future therapeutic target for metabolic diseases. Increasing evidence suggests a link between ucOC and cardiovascular disease (CVD) development; however, the exact relationship is conflicting and unclear.
SCOPE OF REVIEW
The aim of this review was to summarise the current research examining the interaction between OC and vascular dysfunction, the initiating stage in the development of atherosclerosis and CVD.
MAJOR CONCLUSIONS
In humans, the association between OC and vascular function is inconsistent. Several studies report that total OC (tOC) is associated with adverse function or beneficial function, whereas others report that tOC and ucOC has no effect on vascular function. The conflicting data are likely due to several methodological inconsistencies, in particular the lack of studies reporting circulating ucOC levels. In animal models, the direct administration of ucOC to isolated blood vessels ex vivo produced minimal changes in endothelial function, but importantly, no adverse responses. Finally, in human endothelial and vascular smooth muscle cells, ucOC treatment did not influence classical markers of cellular function, including endothelin-1, vascular adhesion molecule-1 and monocyte chemoattractant protein-1 after exposure to high glucose and inflammatory conditions. The lack of adverse effects in ex vivo and in vitro studies suggests that ucOC may be targeted as a future therapeutic for metabolic diseases, without the risk of detrimental effects in the vasculature. However, further studies are needed to confirm these findings and to investigate whether there is a direct beneficial influence of ucOC.
Topics: Animals; Atherosclerosis; Biomarkers; Bone and Bones; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Endothelial Cells; Humans; Osteocalcin; Receptors, G-Protein-Coupled
PubMed: 33684607
DOI: 10.1016/j.molmet.2021.101205 -
Bone Jan 2016Osteocalcin is among the most abundant proteins in bone and is produced exclusively by osteoblasts. Initially believed to be an inhibitor of bone mineralization, recent... (Review)
Review
Osteocalcin is among the most abundant proteins in bone and is produced exclusively by osteoblasts. Initially believed to be an inhibitor of bone mineralization, recent studies suggest a broader role for osteocalcin that extends to the regulation of whole body metabolism, reproduction, and cognition. Circulating undercarboxylated osteocalcin, which is regulated by insulin, acts in a feed-forward loop to increase β-cell proliferation as well as insulin production and secretion, while skeletal muscle and adipose tissue respond to osteocalcin by increasing their sensitivity to insulin. Osteocalcin also acts in the brain to increase neurotransmitter production and in the testes to stimulate testosterone production. At least one putative receptor for osteocalcin, Gprc6a, is expressed by adipose, skeletal muscle, and the Leydig cells of the testes and appears to mediate osteocalcin's effects in these tissues. In this review, we summarize these new discoveries, which suggest that the ability of osteocalcin to function both locally in bone and as a hormone depends on a novel post-translational mechanism that alters osteocalcin's affinity for the bone matrix and bioavailability. This article is part of a Special Issue entitled Bone and diabetes.
Topics: Adipose Tissue; Animals; Biomarkers; Diabetes Mellitus; Energy Metabolism; Humans; Insulin Resistance; Osteoblasts; Osteocalcin; Signal Transduction
PubMed: 26055108
DOI: 10.1016/j.bone.2015.05.046 -
The Journal of Experimental Medicine Oct 2017That osteocalcin (OCN) is necessary for hippocampal-dependent memory and to prevent anxiety-like behaviors raises novel questions. One question is to determine whether...
That osteocalcin (OCN) is necessary for hippocampal-dependent memory and to prevent anxiety-like behaviors raises novel questions. One question is to determine whether OCN is also sufficient to improve these behaviors in wild-type mice, when circulating levels of OCN decline as they do with age. Here we show that the presence of OCN is necessary for the beneficial influence of plasma from young mice when injected into older mice on memory and that peripheral delivery of OCN is sufficient to improve memory and decrease anxiety-like behaviors in 16-mo-old mice. A second question is to identify a receptor transducing OCN signal in neurons. Genetic, electrophysiological, molecular, and behavioral assays identify , an orphan G protein-coupled receptor expressed in neurons of the CA3 region of the hippocampus, as transducing OCN's regulation of hippocampal-dependent memory in part through inositol 1,4,5-trisphosphate and brain-derived neurotrophic factor. These results indicate that exogenous OCN can improve hippocampal-dependent memory in mice and identify molecular tools to harness this pathway for therapeutic purposes.
Topics: Aging; Animals; CA3 Region, Hippocampal; Cognition; Electrophysiology; Female; Male; Maze Learning; Memory; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteocalcin; Receptors, G-Protein-Coupled
PubMed: 28851741
DOI: 10.1084/jem.20171320