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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 -
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 -
Bone Mar 2021Acute exercise increases osteocalcin (OC), a marker of bone turnover, and in particular the undercarboxylated form (ucOC). Males and females differ in baseline levels of...
INTRODUCTION
Acute exercise increases osteocalcin (OC), a marker of bone turnover, and in particular the undercarboxylated form (ucOC). Males and females differ in baseline levels of total OC and it is thought the hormonal milieu may be driving these differences. Males and females adapt differently to the same exercise intervention, however it is unclear whether the exercise effects on OC are also sex-specific. We tested whether the responses of OC and its forms to acute High Intensity Interval Exercise (HIIE) and High Intensity Interval Training (HIIT) differed between males and females. Secondly, we examined whether sex hormones vary with OC forms within sexes to understand if these are driving factor in any potential sex differences.
METHODS
Total OC (tOC), undercarboxylated OC (ucOC), and carboxylated OC (cOC) were measured in serum of 96 healthy participants from the Gene SMART cohort (74 males and 22 females) at rest, immediately after, and 3 h after a single bout of HIIE, and at rest, 48 h after completing a four week HIIT intervention. Baseline testosterone and estradiol were also measured for a subset of the cohort (Males = 38, Females = 20). Linear mixed models were used to a) uncover the sex-specific effects of acute exercise and short-term training on OC forms and b) to examine whether the sex hormones were associated with OC levels.
RESULTS
At baseline, males had higher levels of tOC, cOC, and ucOC than females (q < 0.01). In both sexes tOC, and ucOC increased to the same extent after acute HIIE. At baseline, in males only, higher testosterone was associated with higher ucOC (β = 3.37; q < 0.046). Finally, tOC and ucOC did not change following 4 weeks of HIIT.
CONCLUSION/DISCUSSION
While there were no long-term changes in OC and its forms. tOC and ucOC were transiently enhanced after a bout of HIIE similarly in both sexes. This may be important in metabolic signalling in skeletal muscle and bone suggesting that regular exercise is needed to maintain these benefits. Overall, these data suggest that the sex differences in exercise adaptations do not extend to the bone turnover marker, OC.
Topics: Biomarkers; Bone Remodeling; Female; High-Intensity Interval Training; Humans; Male; Osteocalcin; Sex Factors; Testosterone
PubMed: 33338665
DOI: 10.1016/j.bone.2020.115818 -
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 -
Journal of Cachexia, Sarcopenia and... Jun 2023The progressive deterioration of tissue-tissue crosstalk with aging causes a striking impairment of tissue homeostasis and functionality, particularly in the...
BACKGROUND
The progressive deterioration of tissue-tissue crosstalk with aging causes a striking impairment of tissue homeostasis and functionality, particularly in the musculoskeletal system. Rejuvenation of the systemic and local milieu via interventions such as heterochronic parabiosis and exercise has been reported to improve musculoskeletal homeostasis in aged organisms. We have shown that Ginkgolide B (GB), a small molecule from Ginkgo biloba, improves bone homeostasis in aged mice by restoring local and systemic communication, implying a potential for maintaining skeletal muscle homeostasis and enhancing regeneration. In this study, we investigated the therapeutic efficacy of GB on skeletal muscle regeneration in aged mice.
METHODS
Muscle injury models were established by barium chloride induction into the hind limb of 20-month-old mice (aged mice) and into C2C12-derived myotubes. Therapeutic efficacy of daily administrated GB (12 mg/kg body weight) and osteocalcin (50 μg/kg body weight) on muscle regeneration was assessed by histochemical staining, gene expression, flow cytometry, ex vivo muscle function test and rotarod test. RNA sequencing was used to explore the mechanism of GB on muscle regeneration, with subsequent in vitro and in vivo experiments validating these findings.
RESULTS
GB administration in aged mice improved muscle regeneration (muscle mass, P = 0.0374; myofiber number/field, P = 0.0001; centre nucleus, embryonic myosin heavy chain-positive myofiber area, P = 0.0144), facilitated the recovery of muscle contractile properties (tetanic force, P = 0.0002; twitch force, P = 0.0005) and exercise performance (rotarod performance, P = 0.002), and reduced muscular fibrosis (collagen deposition, P < 0.0001) and inflammation (macrophage infiltration, P = 0.03). GB reversed the aging-related decrease in the expression of osteocalcin (P < 0.0001), an osteoblast-specific hormone, to promote muscle regeneration. Exogenous osteocalcin supplementation was sufficient to improve muscle regeneration (muscle mass, P = 0.0029; myofiber number/field, P < 0.0001), functional recovery (tetanic force, P = 0.0059; twitch force, P = 0.07; rotarod performance, P < 0.0001) and fibrosis (collagen deposition, P = 0.0316) in aged mice, without an increased risk of heterotopic ossification.
CONCLUSIONS
GB treatment restored the bone-to-muscle endocrine axis to reverse aging-related declines in muscle regeneration and thus represents an innovative and practicable approach to managing muscle injuries. Our results revealed the critical and novel role of osteocalcin-GPRC6A-mediated bone-to-muscle communication in muscle regeneration, which provides a promising therapeutic avenue in functional muscle regeneration.
Topics: Mice; Animals; Muscle, Skeletal; Osteocalcin; Bone and Bones; Muscle Fibers, Skeletal; Receptors, G-Protein-Coupled
PubMed: 37076950
DOI: 10.1002/jcsm.13228 -
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 -
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 -
Journal of Orthopaedic Surgery and... Oct 2023The aim of this study was to investigate whether Osteonectin/Secreted protein acidic and rich in cysteine (ON/SPARC) had a two-way dose-dependent regulatory effect on...
OBJECTIVE
The aim of this study was to investigate whether Osteonectin/Secreted protein acidic and rich in cysteine (ON/SPARC) had a two-way dose-dependent regulatory effect on osteoblast mineralization and its molecular mechanism.
METHODS
Initially, different concentrations of ON were added in osteoblasts, and the gene of bone sialoprotein (BSP), osteocalcin (OCN), osteopontin (OPN) and alkaline phosphatase (ALP) were detected using reverse-transcription quantitative polymerase chain reaction (RT-PCR). Secondly, based on the above results, the Optima and inhibitory concentration of ON for osteoblast mineralization were determined and regrouped, the Control group was also set up, and the gene detections of Collagen 1 (Col 1), Discoidin domain receptor 2 (DDR2) and p38 mitogen‑activated protein kinase were added using RT-PCR. In the third stage of the experiment, osteoblasts were pretreated with 0.4Mm ethyl-3,4-dihydroxybenzoate (DHB) (a specific inhibitor of collagen synthesis) for 3 h before adding the optima SPARC, the gene and protein expressions of OCN, OPN, BSP, ALP, DDR2, ALP, Col 1, DDR2 and P38 were detected by RT‑qPCR and western blot analysis, and the mineralized nodules were observed by alizarin red staining.
RESULTS
The results showed that the expression of OCN, OPN, BSP, ALP, DDR2, ALP, Col 1, DDR2 and P38 genes and proteins in osteoblasts were significantly enhanced by 1 ug/ml ON, 100 ug/ml ON or 1 ug/ml ON added with 3,4 DHB significantly inhibited the expressions of DDR2, P38 and the above-mentioned mineralization indexes, and significantly reduced the formation of mineralized nodules.
CONCLUSION
This study suggested that ON had a bidirectional dose-dependent regulatory effect on osteoblast mineralization, and the activation of P38 pathway by collagen binding to DDR2 was also an important molecular mechanism.
Topics: Humans; Osteonectin; Osteocalcin; Calcinosis; Integrin-Binding Sialoprotein; Collagen; Osteoblasts; Cell Differentiation; Osteogenesis
PubMed: 37807073
DOI: 10.1186/s13018-023-04250-1 -
Frontiers in Endocrinology 2023Bone and skeletal muscle work in coordination to maintain the function of the musculoskeletal system, in which skeletal muscle contraction drives the movement of the... (Review)
Review
Bone and skeletal muscle work in coordination to maintain the function of the musculoskeletal system, in which skeletal muscle contraction drives the movement of the bone lever system while bone provides insert sites for skeletal muscle through the bone-muscle junction. Existing evidence suggests that factors secreted by skeletal muscle and bone mediate the interaction between the two tissues. Herein, we focused on the relationship between skeletal muscle and bone and the underlying mechanism of the interaction. Exercise can promote bone strength and secrete osteocalcin and insulin-like growth factor I into the blood, thus improving muscle quality. In addition, exercise can also promote myostatin, interleukin-6, Irisin, and apelin in muscles to enter the blood so that they can act on bones to maintain the balance between bone absorption and bone formation. There is a special regulatory axis interleukin-6/osteocalcin between myokines and osteokines, which is mainly influenced by exercise. Therefore, we pay attention to the important factors in the bone-muscle intersection that are affected by exercise, which were found or their functions were expanded, which strengthened the connection between organs of the whole body, highlighting the importance of exercise and contributing to the diagnosis, prevention, and treatment of osteoporosis and sarcopenia in the clinic.
Topics: Bone and Bones; Exercise; Interleukin-6; Muscle, Skeletal; Osteocalcin
PubMed: 38239981
DOI: 10.3389/fendo.2023.1287972 -
Calcified Tissue International Feb 2023Vitamin K, a cofactor for the γ-glutamyl carboxylase enzyme, is required for the post-translational activation of osteocalcin and matrix Gla protein, which play a key... (Review)
Review
Vitamin K, a cofactor for the γ-glutamyl carboxylase enzyme, is required for the post-translational activation of osteocalcin and matrix Gla protein, which play a key role in bone and muscle homeostasis. In vivo and in vitro models for osteoporosis and sarcopenia suggest the vitamin K could exert a positive effect in both conditions. In bone, it increases osteoblastogenesis, whilst decreases osteoclast formation and function. In muscle, it is associated with increased satellite cell proliferation and migration and might play a role in energy metabolism. Observational trials suggest that high levels of vitamin K are associated with increased bone mineral density and reduced fracture risk. However, interventional studies for vitamin K supplementation yielded conflicting results. Clinical trials in sarcopenia suggest that vitamin K supplementation could improve muscle mass and function. One of the main limitations on the vitamin K studies are the technical challenges to measure its levels in serum. Thus, they are obtained from indirect sources like food questionnaires, or levels of undercarboxylated proteins, which can be affected by other environmental or biological processes. Although current research appoints to a beneficial effect of vitamin K in bone and muscle, further studies overcoming the current limitations are required in order to incorporate this supplementation in the clinical management of patients with osteosarcopenia.
Topics: Humans; Vitamin K; Bone Density; Sarcopenia; Bone and Bones; Osteocalcin; Muscles
PubMed: 35150288
DOI: 10.1007/s00223-022-00955-3