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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 -
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 -
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 -
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 -
Food & Function Apr 2020Previous studies did not draw a consistent conclusion about the effects of vitamin K combined with vitamin D on human skeletal quality. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Previous studies did not draw a consistent conclusion about the effects of vitamin K combined with vitamin D on human skeletal quality.
METHOD AND FINDINGS
A comprehensive search on Web of Science, PubMed, Embase and the Cochrane Library (from 1950 to February 2020) and bibliographies of relevant articles was undertaken, with the meta-analysis of eight randomized controlled trials (RCTs) including a total of 971 subjects. Vitamin K combined with vitamin D significantly increased the total bone mineral density (BMD): the pooled effect size was 0.316 [95% CI (confidence interval), 0.031 to 0.601]. A significant decrease in undercarboxylated osteocalcin (-0.945, -1.113 to -0.778) can be observed with the combination of vitamin K and D. Simultaneously, subgroup analysis showed that K2 or vitamin K (not specified) supplement was less than 500 μg d-1, which when combined with vitamin D can significantly increase the total BMD compared with the control group fed a normal diet or the group with no treatment (0.479, 0.101 to 0.858 and 0.570, 0.196 to 0.945).
CONCLUSIONS
The combination of vitamin K and D can significantly increase the total BMD and significantly decrease undercarboxylated osteocalcin, and a more favorable effect is expected when vitamin K2 is used.
Topics: Bone Density; Bone and Bones; Databases, Factual; Dietary Supplements; Humans; Osteocalcin; Randomized Controlled Trials as Topic; Vitamin D; Vitamin K; Vitamin K 2
PubMed: 32219282
DOI: 10.1039/c9fo03063h -
Biochemical Pharmacology May 2017Bone has traditionally been regarded as a static structural organ that supports movement of the body and protects the internal organs. However, evidence has been... (Review)
Review
Bone has traditionally been regarded as a static structural organ that supports movement of the body and protects the internal organs. However, evidence has been accumulated in the past decade showing that bone also functions as an endocrine organ that regulates systemic glucose and energy metabolism. Osteocalcin, an osteoblast-specific secreted protein, acts as a hormone by stimulating insulin production and increasing energy expenditure and insulin sensitivity in target organs. Animal studies have shown that an increase in the circulating concentration of osteocalcin, including via exogenous application of the protein, prevents obesity and glucose intolerance. Moreover, a number of epidemiological analyses support the role of osteocalcin in the regulation of glucose and energy homeostasis in humans. Therefore, it has been suggested that osteocalcin could be a feasible preventive or therapeutic agent for metabolic disorders. In this review, we summarize the current knowledge regarding the endocrine functions of osteocalcin and its various modes of action.
Topics: Animals; Endocrine Glands; Female; Glucose; Humans; Male; Osteocalcin; Receptors, Cell Surface
PubMed: 28189726
DOI: 10.1016/j.bcp.2017.02.001 -
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 -
Journal of Bone and Mineral Metabolism Jul 2016An increasing amount of data indicate that osteocalcin is an endocrine hormone which regulates energy metabolism, male fertility and brain development. However, the... (Review)
Review
An increasing amount of data indicate that osteocalcin is an endocrine hormone which regulates energy metabolism, male fertility and brain development. However, the detailed functions and mechanism of osteocalcin are not well understood and conflicting results have been obtained from researchers worldwide. In the present review, we summarize the progress of osteocalcin studies over the past 40 years, focusing on the structure of carboxylated and undercarboxylated osteocalcin, new functions and putative receptors, the role of osteocalcin in bone remodeling, specific expression and regulation in osteoblasts, and new indices for clinical studies. The complexity of osteocalcin in completely, uncompletely and non-carboxylated forms may account for the discrepancies in its tertiary structure and clinical results. Moreover, the extensive expression of osteocalcin and its putative receptor GPRC6A imply that there are new physiological functions and mechanisms of action of osteocalcin to be explored. New discoveries related to osteocalcin function will assist its potential clinical application and physiological theory, but comprehensive investigations are required.
Topics: Animals; Biomedical Research; Bone Remodeling; Energy Metabolism; Female; Fertility; Humans; Male; Osteocalcin; Receptors, G-Protein-Coupled
PubMed: 26747614
DOI: 10.1007/s00774-015-0734-7 -
Microbiome Jan 2021Parkinson's disease (PD) is a neurodegenerative disorder with no absolute cure. The evidence of the involvement of gut microbiota in PD pathogenesis suggests the need to...
BACKGROUND
Parkinson's disease (PD) is a neurodegenerative disorder with no absolute cure. The evidence of the involvement of gut microbiota in PD pathogenesis suggests the need to identify certain molecule(s) derived from the gut microbiota, which has the potential to manage PD. Osteocalcin (OCN), an osteoblast-secreted protein, has been shown to modulate brain function. Thus, it is of interest to investigate whether OCN could exert protective effect on PD and, if yes, whether the underlying mechanism lies in the subsequent changes in gut microbiota.
RESULTS
The intraperitoneal injection of OCN can effectively ameliorate the motor deficits and dopaminergic neuronal loss in a 6-hydroxydopamine-induced PD mouse model. The further antibiotics treatment and fecal microbiota transplantation experiments confirmed that the gut microbiota was required for OCN-induced protection in PD mice. OCN elevated Bacteroidetes and depleted Firmicutes phyla in the gut microbiota of PD mice with elevated potential of microbial propionate production and was confirmed by fecal propionate levels. Two months of orally administered propionate successfully rescued motor deficits and dopaminergic neuronal loss in PD mice. Furthermore, AR420626, the agonist of FFAR3, which is the receptor of propionate, mimicked the neuroprotective effects of propionate and the ablation of enteric neurons blocked the prevention of dopaminergic neuronal loss by propionate in PD mice.
CONCLUSIONS
Together, our results demonstrate that OCN ameliorates motor deficits and dopaminergic neuronal loss in PD mice, modulating gut microbiome and increasing propionate level might be an underlying mechanism responsible for the neuroprotective effects of OCN on PD, and the FFAR3, expressed in enteric nervous system, might be the main action site of propionate. Video abstract.
Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Disease Progression; Dopaminergic Neurons; Fecal Microbiota Transplantation; Gastrointestinal Microbiome; Infusions, Parenteral; Male; Mice; Neuroprotective Agents; Osteocalcin; Oxidopamine; Parkinson Disease; Propionates; Receptors, G-Protein-Coupled
PubMed: 33517890
DOI: 10.1186/s40168-020-00988-6