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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 -
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 -
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 -
International Journal of Molecular... Feb 2020Bone and muscle represent a single functional system and are tightly connected to each other. Indeed, diseases characterized by alterations of muscle physiology have... (Review)
Review
Bone and muscle represent a single functional system and are tightly connected to each other. Indeed, diseases characterized by alterations of muscle physiology have effects on bone remodeling and structure and vice versa. Muscle influence on bone has been deeply studied, and recent studies identified irisin as new molecule involved in this crosstalk. Muscle regulation by bone needs to be extensively investigated since in the last few years osteocalcin was recognized as a key molecule in the bone-muscle interaction. Osteocalcin can exist in two forms with different degrees of carboxylation. The undercarboxylated form of osteocalcin is a hormone released by the bone matrix during the osteoclast bone resorption and can bind its G-protein coupled receptor GPRC6A expressed in the muscle, thus regulating its function. Recently, this hormone was described as an antiaging molecule for its ability to regulate bone, muscle and cognitive functions. Indeed, the features of this bone-related hormone were used to test a new therapeutic approach for sarcopenia, since injection of osteocalcin in older mice induces the acquirement of physical abilities of younger animals. Even if this approach should be tested in humans, osteocalcin represents the most surprising molecule in endocrine regulation by the skeleton.
Topics: Animals; Bone Resorption; Bone and Bones; Exercise; Humans; Muscle, Skeletal; Musculoskeletal Physiological Phenomena; Osteocalcin; Osteoclasts; Receptors, G-Protein-Coupled
PubMed: 32053970
DOI: 10.3390/ijms21041178 -
Head and Neck Pathology Jun 2023Gingival fibromas (GFs) are fibrous lesions of the gingiva that are not well defined in the literature. They are histologically similar to peripheral ossifying fibromas...
PURPOSE
Gingival fibromas (GFs) are fibrous lesions of the gingiva that are not well defined in the literature. They are histologically similar to peripheral ossifying fibromas (POFs), both being characterized as cellular proliferations of dense fibrous tissue, with POFs differing in that they demonstrate foci of calcification. This study aims to expand upon the immunohistochemical characterization of GFs, and to confirm their osteoblastic phenotype.
METHODS
Formalin fixed, paraffin embedded GFs, POFs and fibroepithelial polyps (FEPs) of the gingiva were examined. Immunohistochemical staining was performed for special AT-rich sequence binding protein 2 (SATB2), runt-related transcription factor 2 (RUNX2), osteocalcin and alpha-smooth muscle actin (αSMA). Sections were evaluated by light microscopy and the immunohistochemical staining patterns were assigned immunoreactive scores (IRS) based on percentage of stained cells and intensity of staining.
RESULTS
GFs, POFs, and FEPs of the gingiva expressed osteoblastic markers SATB2, RUNX2 and osteocalcin. GFs and POFs expressed αSMA while FEPs of the gingiva did not. GFs and POFs had similar staining patterns of SATB2, RUNX2 and αSMA.
DISCUSSION
These findings demonstrate that GFs and POFs exhibit a similar immunohistochemical profile, and supports a theory that GFs are osteoblastic lesions possibly related to POFs.
Topics: Humans; Core Binding Factor Alpha 1 Subunit; Osteocalcin; Immunohistochemistry; Fibroma, Ossifying; Gingival Neoplasms; Calcinosis
PubMed: 36472794
DOI: 10.1007/s12105-022-01493-y -
EMBO Reports Feb 2024Many physiological osteocalcin-regulated functions are affected in adult offspring of mothers experiencing unhealthy pregnancy. Furthermore, osteocalcin signaling during...
Many physiological osteocalcin-regulated functions are affected in adult offspring of mothers experiencing unhealthy pregnancy. Furthermore, osteocalcin signaling during gestation influences cognition and adrenal steroidogenesis in adult mice. Together these observations suggest that osteocalcin may broadly function during pregnancy to determine organismal homeostasis in adult mammals. To test this hypothesis, we analyzed in unchallenged wildtype and Osteocalcin-deficient, newborn and adult mice of various genotypes and origin maintained on different genetic backgrounds, the functions of osteocalcin in the pancreas, liver and testes and their molecular underpinnings. This analysis revealed that providing mothers are Osteocalcin-deficient, Osteocalcin haploinsufficiency in embryos hampers insulin secretion, liver gluconeogenesis, glucose homeostasis, testes steroidogenesis in adult offspring; inhibits cell proliferation in developing pancreatic islets and testes; and disrupts distinct programs of gene expression in these organs and in the brain. This study indicates that osteocalcin exerts dominant functions in most organs it influences. Furthermore, through their synergistic regulation of multiple physiological functions, osteocalcin of maternal and embryonic origins contributes to the establishment and maintenance of organismal homeostasis in newborn and adult offspring.
Topics: Animals; Female; Humans; Mice; Pregnancy; Blood Glucose; Homeostasis; Insulin; Insulin Secretion; Mammals; Osteocalcin; Prenatal Exposure Delayed Effects
PubMed: 38228788
DOI: 10.1038/s44319-023-00031-3