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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 -
Journal of Cellular Biochemistry Sep 2019The nature of muscle-bone crosstalk has been historically considered to be only mechanical, where the muscle is the load applier while bone provides the attachment... (Review)
Review
The nature of muscle-bone crosstalk has been historically considered to be only mechanical, where the muscle is the load applier while bone provides the attachment sites. However, this dogma has been challenged with the emerging notion that bone and muscle act as secretory endocrine organs affect the function of each other. Biochemical crosstalk occurs through myokines such as myostatin, irisin, interleukin (IL)-6, IL-7, IL-15, insulin-like growth factor-1, fibroblast growth factor (FGF)-2, and β-aminoisobutyric acid and through bone-derived factors including FGF23, prostaglandin E , transforming growth factor β, osteocalcin, and sclerostin. Aside from the biochemical and mechanical interaction, additional factors including aging, circadian rhythm, nervous system network, nutrition intake, and exosomes also have effects on bone-muscle crosstalk. Here, we summarize the current research progress in the area, which may be conductive to identify potential novel therapies for the osteoporosis and sarcopenia, especially when they develop in parallel.
Topics: Aging; Bone and Bones; Circadian Rhythm; Fibroblast Growth Factor-23; Humans; Muscle Proteins; Muscle, Skeletal; Nervous System Physiological Phenomena; Osteocalcin; Protein Binding; Signal Transduction
PubMed: 31106446
DOI: 10.1002/jcb.28946 -
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 -
Frontiers in Public Health 2022Vitamin K (VK) as a nutrient, is a cofactor in the carboxylation of osteocalcin (OC), which can bind with hydroxyapatite to promote bone mineralization and increase bone... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Vitamin K (VK) as a nutrient, is a cofactor in the carboxylation of osteocalcin (OC), which can bind with hydroxyapatite to promote bone mineralization and increase bone strength. However, some studies have been inconsistent on whether vitamin K2 (VK2) can maintain or improve bone mineral density (BMD) and reduce the incidence of fractures in postmenopausal women. Therefore, the main objective of this meta-analysis was to determine the effect of VK2 as a nutritional supplement on BMD and fracture incidence in postmenopausal women.
METHODS
We searched PubMed, EMBASE, and Cochrane Library databases (published before March 17, 2022) and then extracted and pooled data from all randomized controlled trials (RCTs) that met the inclusion criteria.
RESULTS
Sixteen RCTs with a total of 6,425 subjects were included in this meta-analysis. The overall effect test of 10 studies showed a significant improvement in lumbar spine BMD (BMD LS) ( = 0.006) with VK2. The subgroup analysis of VK2 combination therapy showed that BMD LS was significantly maintained and improved with the administration of VK2 ( = 0.03). The overall effect test of the six RCTs showed no significant difference in fracture incidence between the two groups (RR=0.96, P=0.65). However, after excluding one heterogeneous study, the overall effect test showed a significant reduction in fracture incidence with VK2 (RR = 0.43, = 0.01). In addition, this meta-analysis showed that VK2 reduced serum undercarboxylated osteocalcin (uc-OC) levels and the ratio of uc-OC to cOC in both subgroups of VK2 combined intervention and alone. However, for carboxylated osteocalcin (cOC), both subgroup analysis and overall effect test showed no significant effect of VK2 on it. And the pooled analysis of adverse reactions showed no significant difference between the VK2 and control groups (RR = 1.03, 95%CI 0.87 to 1.21, = 0.76).
CONCLUSIONS
The results of this meta-analysis seem to indicate that VK2 supplementation has a positive effect on the maintenance and improvement of BMD LS in postmenopausal women, and it can also reduce the fracture incidence, serum uc-OC levels and the ratio of uc-OC to cOC. In conclusion, VK2 can indirectly promote bone mineralization and increase bone strength.
Topics: Bone Density Conservation Agents; Female; Humans; Osteocalcin; Osteoporosis, Postmenopausal; Randomized Controlled Trials as Topic; Vitamin K 2
PubMed: 36033779
DOI: 10.3389/fpubh.2022.979649 -
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 -
ACS Applied Materials & Interfaces Aug 2020Designing bone adhesives with adhesiveness, antideformation, biocompatibility, and biofunctional effects has great practical significance for bone defect reconstructive...
Designing bone adhesives with adhesiveness, antideformation, biocompatibility, and biofunctional effects has great practical significance for bone defect reconstructive treatment, especially for bone graft repair surgery. Here, we designed zeolitic imidazolate framework-8 nanoparticle (ZIF-8 NP)-modified catechol-chitosan (CA-CS) multifunctional hydrogels (CA-CS/Z) to stabilize the bone graft environment, ensure blood supply, promote osteogenic differentiation, and accelerate bone reconstruction. Characterizations confirmed the successful synthesis of CA-CS/Z hydrogels. Hydrogels exhibited advanced rheological properties, reliable mechanical strength, and excellent adhesion for clinical applications. Based on excellent biocompatibility, it could enhance paracrine of the vascular endothelial growth factor (VEGF) in rat bone marrow mesenchymal stem cells (rBMSCs) to ensure blood supply reconstruction in bone defect areas. Furthermore, the ZIF-8 NPs released from the hydrogels could also up-regulate the production and secretion of alkaline phosphatase, collagen 1, and osteocalcin, promoting the osteogenic differentiation of rBMSCs. In addition, the antibacterial properties of CA-CS/Z could also be observed. In vivo experiments further provided a powerful proof that CA-CS/Z promoted vascularized osteogenesis in wound areas by stabilizing bone graft materials and greatly accelerated the speed and healing of bone reconstruction. These results indicate the promising potential of CA-CS/Z hydrogels with promoting implantation stability, angiogenesis, and osteogenesis for bone regeneration applications.
Topics: Adhesives; Alkaline Phosphatase; Anti-Bacterial Agents; Biocompatible Materials; Bone Regeneration; Bone and Bones; Catechols; Cell Differentiation; Cells, Cultured; Chitosan; Collagen; Escherichia coli; Gene Expression Regulation; Humans; Hydrogels; Mesenchymal Stem Cells; Nanoparticles; Osteocalcin; Osteogenesis; Rheology; Staphylococcus aureus; Surface Properties; Tissue Engineering; Tissue Scaffolds; Vascular Endothelial Growth Factor A; Wound Healing; Zeolites
PubMed: 32814397
DOI: 10.1021/acsami.0c12090 -
Journal of Oral Biosciences Sep 2020Osteocalcin is the most abundant non-collagenous protein in bone and is specifically expressed in osteoblasts. Previous studies using osteocalcin-deficient (Ocn) mice... (Review)
Review
BACKGROUND
Osteocalcin is the most abundant non-collagenous protein in bone and is specifically expressed in osteoblasts. Previous studies using osteocalcin-deficient (Ocn) mice demonstrated that osteocalcin inhibits bone formation, and serum uncarboxylated osteocalcin functions as a hormone that improves glucose metabolism, induces testosterone synthesis in the testes, and maintains muscle mass. Furthermore, the relationship between serum osteocalcin and glucose metabolism or cardiovascular risk in humans has been reported. However, new Ocn mice exhibited different phenotypes.
HIGHLIGHT
Bone volume, formation, and resorption were normal in the new Ocn mice. The orientation of collagen fibers was parallel to the bone longitudinal direction and the size of apatite crystals was normal, but the c-axis of apatite crystals was random and bone strength was reduced in new Ocn mice. Glucose metabolism, testosterone synthesis, and muscle mass were normal in new Ocn mice. Exercise improved glucose metabolism and increased bone formation, leading to an increase in the serum osteocalcin level, which is a marker for bone formation.
CONCLUSION
Contrary to previous findings, new Ocn mice revealed that osteocalcin has no function in the regulation of bone quantity, but instead, functions to direct the parallel alignment of the c-axis of apatite crystals with collagen fibrils. Moreover, it has no physiological function as a hormone that regulates glucose metabolism, testosterone synthesis, or muscle mass. These controversial phenotypes require further investigation. The relationship of serum osteocalcin with glucose metabolism or cardiovascular risk suggests the importance of exercise for their improvement.
Topics: Animals; Apatites; Bone and Bones; Male; Mice; Osteoblasts; Osteocalcin; Osteogenesis
PubMed: 32535287
DOI: 10.1016/j.job.2020.05.004 -
Cell Reports May 2023Vitamin K is a micronutrient necessary for γ-carboxylation of glutamic acids. This post-translational modification occurs in the endoplasmic reticulum (ER) and affects...
Vitamin K is a micronutrient necessary for γ-carboxylation of glutamic acids. This post-translational modification occurs in the endoplasmic reticulum (ER) and affects secreted proteins. Recent clinical studies implicate vitamin K in the pathophysiology of diabetes, but the underlying molecular mechanism remains unknown. Here, we show that mouse β cells lacking γ-carboxylation fail to adapt their insulin secretion in the context of age-related insulin resistance or diet-induced β cell stress. In human islets, γ-carboxylase expression positively correlates with improved insulin secretion in response to glucose. We identify endoplasmic reticulum Gla protein (ERGP) as a γ-carboxylated ER-resident Ca-binding protein expressed in β cells. Mechanistically, γ-carboxylation of ERGP protects cells against Ca overfilling by diminishing STIM1 and Orai1 interaction and restraining store-operated Ca entry. These results reveal a critical role of vitamin K-dependent carboxylation in regulation of Ca flux in β cells and in their capacity to adapt to metabolic stress.
Topics: Mice; Animals; Humans; Vitamin K; Osteocalcin; Protein Processing, Post-Translational; Insulin; Stress, Physiological; Calcium
PubMed: 37171959
DOI: 10.1016/j.celrep.2023.112500