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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 -
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 -
Molecular Medicine Reports Jan 2019Osteocalcin is no longer regarded as a molecule exclusive to bone remodeling and osteogenesis, but as a hormone with manifold functions. The discovery of the interaction... (Review)
Review
Osteocalcin is no longer regarded as a molecule exclusive to bone remodeling and osteogenesis, but as a hormone with manifold functions. The discovery of the interaction of osteocalcin with the G protein‑coupled receptor family C group 6‑member A (GPRC6A) receptor has accompanied the characterization of several roles that this peptide serves in body regulation and homeostasis. These roles include the modulation of memory in the brain, fertility in the testis, fat accumulation in the liver, incretins release in the intestine and adaptation to exercise in muscle, in addition to the well‑known effects on β‑cell proliferation, insulin release and adiponectin secretion. The aim of the present review was to provide a practical update of the multi‑organ effects that osteocalcin exerts through its interaction with GPRC6A and the clinical implications of this.
Topics: Animal Structures; Animals; Homeostasis; Humans; Osteocalcin; Receptors, G-Protein-Coupled
PubMed: 30431093
DOI: 10.3892/mmr.2018.9627 -
Endocrinology Apr 2021A new schema proposes that the bone-derived osteocalcin (Ocn) peptide hormone activates the G-protein-coupled receptor GPRC6A to directly regulate glucose and fat... (Review)
Review
A new schema proposes that the bone-derived osteocalcin (Ocn) peptide hormone activates the G-protein-coupled receptor GPRC6A to directly regulate glucose and fat metabolism in liver, muscle, and fat, and to stimulate the release of metabolism-regulating hormones, including insulin, fibroblast growth factor 21, glucagon-like peptide 1, testosterone, and interleukin 6. Ocn/GPRC6A activation has also been implicated in cancer progression. GPRC6A is activated by cations, amino acids, and testosterone. The multiligand specificity, the regulation of energy metabolism in diverse tissues, and the coordinated release of metabolically active hormones make the GPRC6A endocrine networks unique. Recently, the significance of Ocn/GPRCA has been questioned. There is a lack of metabolic abnormalities in newly created genetically engineered Ocn- and Gprc6a-deficient mouse models. There are also paradoxical observations that GPRC6A may function as a tumor suppressor. In addition, discordant published studies have cast doubt on the function of the most prevalent uniquely human GPRC6A-KGKY polymorphism. Explanations for these divergent findings are elusive. We provide evidence that the metabolic susceptibility of genetically engineered Ocn- and Gprc6a-deficient mice is influenced by environmental challenges and genetic differences in mouse strains. In addition, the GPRC6A-KGKY polymorphism appears to be a gain-of-function variant. Finally, alternatively spliced isoforms of GPRC6A may alter ligand specificity and signaling that modulate oncogenic effects. Thus, genetic, post-translational and environmental factors likely account for the variable results regarding the functions of GPRC6A in animal models. Pending additional information, GPRC6A should remain a potential therapeutic target for regulating energy and fat metabolism, hormone production, and cancer progression.
Topics: Animals; Endocrine System; Fibroblast Growth Factors; Glucagon-Like Peptide 1; Humans; Osteocalcin; Receptors, G-Protein-Coupled; Signal Transduction; Testosterone
PubMed: 33474566
DOI: 10.1210/endocr/bqab011 -
Nature Reviews. Endocrinology Mar 2022
Topics: Humans; Osteocalcin
PubMed: 34992234
DOI: 10.1038/s41574-021-00632-9 -
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 -
Medecine Sciences : M/S Apr 2017Osteocalcin, a protein secreted by osteoblasts, is recognized as a biomarker of bone mineralization. Besides, animal experimental studies have shown that osteocalcin... (Review)
Review
Osteocalcin, a protein secreted by osteoblasts, is recognized as a biomarker of bone mineralization. Besides, animal experimental studies have shown that osteocalcin could play an important role in glucose metabolism. Over the course of the last decade, this theory has been investigated in several human studies. Most of the results obtained from these reports support a positive correlation between total and undercarboxylated osteocalcin and insulin secretion/sensitivity. Studies also corroborate a reverse association with glycemic parameters such as fasting glucose and glycated hemoglobin. Nevertheless, because most of the studies published are observational, it is not possible to yet confirm a direct cause-effect relationship. Research in the field will surely contribute to the development of new pharmacological strategies for the treatment of endocrine diseases.
Topics: Animal Experimentation; Animals; Biomarkers; Clinical Studies as Topic; Endocrine System Diseases; Glucose; Humans; Osteocalcin; Therapies, Investigational
PubMed: 28497738
DOI: 10.1051/medsci/20173304012 -
The International Journal of... Nov 2021Bone has conventionally been considered to be a passive organ that only receives external control, but according to recent findings, it has become clear that bone is an... (Review)
Review
INTRODUCTION
Bone has conventionally been considered to be a passive organ that only receives external control, but according to recent findings, it has become clear that bone is an endocrine organ that actively regulates systemic metabolism through osteocalcin (OC).
METHODS
We focus on the relationship between the brain and bone and summarize the effects of OC on cognitive function as well as the association between OC and improved cognitive function through exercise.
RESULTS
The findings suggest that the decrease in OC produced by bone is responsible for the decrease in cognitive function associated with aging. Furthermore, positive effect of improving cognitive function can generally be recognized in exercise interventions conducted for healthy elderly people and those with MCI, and moderate exercise is particularly effective for dementia prevention.
CONCLUSION
The improving bone health with aging may exert beneficial effects on cognition.
Topics: Aging; Brain; Cognition; Humans; Osteocalcin
PubMed: 32410480
DOI: 10.1080/00207454.2020.1770247 -
Critical Reviews in Clinical Laboratory... 1991Osteocalcin is a small (Mr 5800), very interesting bone specific protein, synthesized by osteoblasts and measured in plasma as a biochemical indicator of bone formation.... (Review)
Review
Osteocalcin is a small (Mr 5800), very interesting bone specific protein, synthesized by osteoblasts and measured in plasma as a biochemical indicator of bone formation. Many immunoassays for osteocalcin have been developed, including radio- and enzymoimmunoassays, with the use of monoclonal and polyclonal antibodies. These are used in many different clinical settings, including bone, kidney, and liver diseases. However, there is a wide range of published values for plasma osteocalcin concentrations in control and patient samples and this has hindered a more widespread adoption of osteocalcin measurement by clinicians. This review discusses how various immunoassays for osteocalcin may contribute to the wide variation of published values and suggests approaches for the development of standardized assays. For example, epitope specificity and immunoreactivity with multiple forms of osteocalcin and osteocalcin peptides in plasma are discussed. It also includes a recent update on interesting clinical applications of osteocalcin.
Topics: Aging; Amino Acid Sequence; Bone Neoplasms; Bone Remodeling; Female; Humans; Hyperthyroidism; Immunoassay; Male; Molecular Sequence Data; Osteocalcin; Osteoporosis; Sex Factors
PubMed: 1930680
DOI: 10.3109/10408369109106867