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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 -
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 -
Reviews in Endocrine & Metabolic... Jun 2015A recent unexpected development of bone biology is that bone is an endocrine organ contributing to the regulation of a number of physiological processes. One of the... (Review)
Review
A recent unexpected development of bone biology is that bone is an endocrine organ contributing to the regulation of a number of physiological processes. One of the functions regulated by bone through osteocalcin, an osteoblast specific hormone, is glucose homeostasis. In this overview, we explain the rationale why we hypothesized that there should be a coordinated endocrine regulation between bone mass and energy metabolism. We then review the experiments that identified the endocrine function of osteocalcin and the cell biology events that allow osteocalcin to become a hormone. We also demonstrate the importance of this regulation to understand whole-body glucose homeostasis in the physiological state and in pathological conditions. Lastly we discuss the epidemiological and genetic evidence demonstrating that this function of osteocalcin is conserved in humans.
Topics: Animals; Bone and Bones; Energy Metabolism; Humans; Insulin; Insulin Secretion; Osteoblasts; Osteocalcin; Protein Processing, Post-Translational; Receptors, G-Protein-Coupled
PubMed: 25577163
DOI: 10.1007/s11154-014-9307-7 -
CNS Neuroscience & Therapeutics Dec 2023As the ovaries age and women transition to menopause and postmenopause, reduced estradiol levels are associated with anxiety and depression. Exercise contributes to...
AIMS
As the ovaries age and women transition to menopause and postmenopause, reduced estradiol levels are associated with anxiety and depression. Exercise contributes to alleviate anxiety and depression and the bone-derived hormone osteocalcin has been reported to be necessary to prevent anxiety-like behaviors. The aim of this study was to investigate the effects of exercise on anxiety behaviors in climacteric mice and whether it was related to osteocalcin.
METHODS
Menopausal mouse model was induced by intraperitoneal injection of 4-vinylcyclohexene diepoxide (VCD). Open field, elevated plus maze, and light-dark tests were used to detect anxious behavior in mice. The content of serum osteocalcin was measured and its correlation with anxiety behavior was analyzed. BRDU and NEUN co-localization cells were detected with immunofluorescence. Western blot was applied to obtain apoptosis-related proteins.
RESULTS
The VCD mice showed obvious anxiety-like behaviors and 10 weeks of treadmill exercise significantly ameliorated the anxiety and increased circulating osteocalcin in VCD mice. Exercise increased the number of BRDU and NEUN co-localization cells in hippocampal dentate gyrus, reduced the number of impaired hippocampal neurons, inhibited the expression of BAX, cleaved Caspase3, and cleaved PARP, promoted the expression of BCL-2. Importantly, circulating osteocalcin levels were positively associated with the improvements of anxiety, the number of BRDU and NEUN co-localization cells in hippocampal dentate gyrus and negatively related to impaired hippocampal neurons.
CONCLUSION
Exercise ameliorates anxiety behavior, promotes hippocampal dentate gyrus neurogenesis, and inhibits hippocampal cell apoptosis in VCD-induced menopausal mice. They are related to circulating osteocalcin, which are increased by exercise.
Topics: Humans; Mice; Animals; Female; Osteocalcin; Neuroprotection; Bromodeoxyuridine; Anxiety; Menopause; Hippocampus; Neurogenesis
PubMed: 37402694
DOI: 10.1111/cns.14324 -
The Netherlands Journal of Medicine Oct 2013For a long time the only functions attributed to the skeleton were locomotion and calcium storage. Over the last decade, this view has changed. Genetic studies in mice... (Review)
Review
For a long time the only functions attributed to the skeleton were locomotion and calcium storage. Over the last decade, this view has changed. Genetic studies in mice have shown that bone metabolism is regulated by the autonomic nervous system and interacts with energy metabolism and reproduction. Osteocalcin, one of the main organic ingredients of the bone matrix, was discovered to stimulate insulin production by the pancreas, as well as energy expenditure and insulin sensitivity. Administration of recombinant osteocalcin to mice on a high fat diet decreased weight gain and insulin resistance. These unanticipated results stimulated studies on osteocalcin and glucose metabolism in humans. This review will discuss these clinical studies and their perspective for the future.
Topics: Animals; Bone and Bones; Glucose; Humans; Insulin; Osteocalcin; Vitamin K
PubMed: 24127499
DOI: No ID Found -
Cell Metabolism Nov 2019We hypothesized that bone evolved, in part, to enhance the ability of bony vertebrates to escape danger in the wild. In support of this notion, we show here that a...
We hypothesized that bone evolved, in part, to enhance the ability of bony vertebrates to escape danger in the wild. In support of this notion, we show here that a bone-derived signal is necessary to develop an acute stress response (ASR). Indeed, exposure to various types of stressors in mice, rats (rodents), and humans leads to a rapid and selective surge of circulating bioactive osteocalcin because stressors favor the uptake by osteoblasts of glutamate, which prevents inactivation of osteocalcin prior to its secretion. Osteocalcin permits manifestations of the ASR to unfold by signaling in post-synaptic parasympathetic neurons to inhibit their activity, thereby leaving the sympathetic tone unopposed. Like wild-type animals, adrenalectomized rodents and adrenal-insufficient patients can develop an ASR, and genetic studies suggest that this is due to their high circulating osteocalcin levels. We propose that osteocalcin defines a bony-vertebrate-specific endocrine mediation of the ASR.
Topics: Adrenal Insufficiency; Adrenalectomy; Adult; Animals; Bone and Bones; Cells, Cultured; Female; Glutamic Acid; Healthy Volunteers; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Neurons; Osteoblasts; Osteocalcin; Parasympathetic Nervous System; Rats; Rats, Sprague-Dawley; Stress, Physiological
PubMed: 31523009
DOI: 10.1016/j.cmet.2019.08.012 -
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 -
ELife Jan 2021Osteocalcin is a bone matrix protein that acts like a hormone when it reaches the blood, and has different effects in mice and humans.
Osteocalcin is a bone matrix protein that acts like a hormone when it reaches the blood, and has different effects in mice and humans.
Topics: Animals; Glycosylation; Hormones; Mice; Osteocalcin
PubMed: 33480844
DOI: 10.7554/eLife.65719 -
Annals of the New York Academy of... Dec 2017Osteocalcin (OC) and osteopontin (OPN) are major non-collagenous proteins (NCPs) involved in bone matrix organization and deposition. In spite of this, it is currently...
Osteocalcin (OC) and osteopontin (OPN) are major non-collagenous proteins (NCPs) involved in bone matrix organization and deposition. In spite of this, it is currently unknown whether OC and OPN alter bone morphology and consequently affect bone fracture resistance. The goal of this study is to establish the role of OC and OPN in the determination of cortical bone size, shape, and mechanical properties. Our results show that Oc and Opn mice were no different from each other or wild type (WT) with respect to bone morphology (P > 0.1). Bones from mice lacking both NCPs (Oc Opn ) were shorter, with thicker cortices and larger cortical areas, compared with the WT, Oc , and Opn groups (P < 0.05), suggesting a synergistic role for NCPs in the determination of bone morphology. Maximum bending load was significantly different among the groups (P = 0.024), while tissue mineral density and measures of stiffness and strength were not different (P > 0.1). We conclude that the removal of both OC and OPN from bone matrix induces morphological adaptation at the structural level to maintain bone strength.
Topics: Animals; Bone Development; Bone and Bones; Male; Mechanical Phenomena; Mice, Inbred C57BL; Mice, Knockout; Osteocalcin; Osteogenesis; Osteopontin
PubMed: 29044594
DOI: 10.1111/nyas.13470 -
Molecular Brain Mar 2019It is now generally accepted that the extra-skeleton functionalities of bone are multifaceted. Its endocrine functions came first to light when it was realized that... (Review)
Review
It is now generally accepted that the extra-skeleton functionalities of bone are multifaceted. Its endocrine functions came first to light when it was realized that osteoblasts, the bone forming cells, maintain energy homeostasis by improving glucose metabolism, insulin sensitivity and energy expenditure through osteocalcin, a multipurpose osteokine secreted by osteoblasts. Recently, the emerging knowledge on the functional aspects of this osteokine expanded to properties including adult and maternal regulation of cognitive functions. Therapeutic potential of this osteokine has also been recently reported in experimental Parkinson's disease models. This review highlights such findings on the functions of osteocalcin in the brain and emphasizes on exploring and analyzing much more in-depth basic and clinical studies.
Topics: Animals; Brain; Cognition; Humans; Motor Neuron Disease; Neuroprotective Agents; Osteocalcin; Signal Transduction
PubMed: 30909971
DOI: 10.1186/s13041-019-0444-5