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Human vascular cell responses to the circulating bone hormone osteocalcin.

ABSTRACT: The purpose of this study was to characterize the direct effects of uncarboxylated osteocalcin (ucOCN) on vascular cell biology in vitro, to assess its potential function in pathophysiological conditions such as atherosclerosis. Human aortic endothelial cells (HAECs) and smooth muscle cells (HASMCs) were treated with ucOCN (0.1-50?ng/ml) and changes in phosphorylation of intracellular signaling proteins, angiogenesis, proliferation, migration, monolayer permeability, and protein secretion were measured. In HAECs, phosphorylated JNK and CREB were decreased with ucOCN (p?

SUBMITTER: Millar SA

PROVIDER: S-EPMC6767466 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Human vascular cell responses to the circulating bone hormone osteocalcin.

Millar Sophie A SA Anderson Susan I SI O'sullivan Saoirse E SE

Journal of cellular physiology 20190426 11

The purpose of this study was to characterize the direct effects of uncarboxylated osteocalcin (ucOCN) on vascular cell biology in vitro, to assess its potential function in pathophysiological conditions such as atherosclerosis. Human aortic endothelial cells (HAECs) and smooth muscle cells (HASMCs) were treated with ucOCN (0.1-50 ng/ml) and changes in phosphorylation of intracellular signaling proteins, angiogenesis, proliferation, migration, monolayer permeability, and protein secretion were m ...[more]

PMID: 31026070

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Circulating osteocalcin as a bone-derived hormone is inversely correlated with body fat in patients with type 1 diabetes.

Project description:The objective of the present study was to investigate the correlations between serum undercarboxylated osteocalcin (ucOC) or osteocalcin (OC) concentrations and %body fat, serum adiponectin and free-testosterone concentration, muscle strength and dose of exogenous insulin in patients with type 1 diabetes. We recruited 73 Japanese young adult patients with childhood-onset type 1 diabetes. All participants were receiving insulin replacement therapy. The correlations between logarithmic serum ucOC or OC concentrations and each parameter were examined. Serum ucOC and OC concentrations were inversely correlated with %body fat (r = -0.319, P = 0.007; r = -0.321, P = 0.006, respectively). Furthermore, multiple linear regression analyses were performed to determine whether or not serum ucOC or OC concentrations were factors associated with %body fat. Serum ucOC and OC concentrations remained significant factors even after adjusting for gender, HbA1c, body weight-adjusted total daily dose of insulin and duration of diabetes (β = -0.260, P = 0.027; β = -0.254, P = 0.031, respectively). However, serum ucOC and OC concentrations were not correlated with serum adiponectin or free-testosterone concentrations, muscle strength or dose of exogenous insulin. In conclusion, our study demonstrates the inverse correlation between serum ucOC or OC concentrations and body fat in patients with type 1 diabetes.

| S-EPMC6499427 | biostudies-literature

Osteocalcin does not influence acute or chronic inflammation in human vascular cells.

Project description:Some human observational studies have suggested an anti-inflammatory role of osteocalcin (OCN). An inflammatory protocol using interferon-? and tumor necrosis factor-? (10?ng/ml) was employed to examine the acute (24?hr) and chronic (144?hr) effects of uncarboxylated OCN (ucOCN) in commercial, primary, subcultured human aortic endothelial cells (HAEC), and human smooth muscle cells (HASMCs). The inflammatory protocol increased phosphorylation of intracellular signaling proteins (CREB, JNK, p38, ERK, AKT, STAT3, STAT5) and increased secretion of adhesion markers (vascular cell adhesion molecule-1, intracellular adhesion molecule-1, monocyte chemoattractant protein-1) and proinflammatory cytokines (interleukin-6 [IL-6], IL-8). After acute inflammation, there were no additive or reductive effects of ucOCN in either cell type. Following chronic inflammation, ucOCN did not affect cell responses, nor did it appear to have any pro- or anti-inflammatory effects when administered acutely or chronically on its own in either cell type. Additionally, ucOCN did not affect lipopolysaccharide (LPS)-induced acute inflammation in HAECs or HASMCs. The findings of this study do not support a causal role for OCN within the models of vascular inflammation chosen. Further confirmatory studies are warranted.

| S-EPMC6972510 | biostudies-literature

Association of Circulating Renin and Aldosterone With Osteocalcin and Bone Mineral Density in African Ancestry Families.

Project description:Hypertension is associated with accelerated bone loss, and the renin-angiotensin-aldosterone system is a key regulator of blood pressure. Although components of this system are expressed in human bone cells, studies in humans are sparse. Thus, we studied the association of circulating renin and aldosterone with osteocalcin and bone mineral density. We recruited 373 African ancestry family members without regard to health status from 6 probands (mean family size: 62 and relative pairs: 1687). Participants underwent a clinical examination, dual-energy x-ray absorptiometry, and quantitative computed tomographic scans. Renin activity, aldosterone concentration, and osteocalcin were measured in fasting blood samples. Aldosterone/renin ratio was calculated as aldosterone concentration/renin activity. All models were analyzed using pedigree-based variance components methods. Full models included adjustment for age, sex, body composition, comorbidities, lifestyle factors, blood pressure, and antihypertensive medication. Higher renin activity was significantly associated with lower total osteocalcin and with higher trabecular bone mineral density (both P<0.01). There were also significant genetic correlations between renin activity and whole-body bone mineral density. There were no associations with aldosterone concentration in any model and results for aldosterone/renin ratio were similar to those for renin activity. This is the first study to report a significant association between renin activity and a marker of bone turnover and bone mineral density in generally healthy individuals. Also, there is evidence for significant genetic pleiotropy and, thus, there may be a shared biological mechanism underlying both the renin-angiotensin-aldosterone system and bone metabolism that is independent of hypertension.

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Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis.

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Osteocalcin modulates parathyroid cell function in human parathyroid tumors.

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| S-EPMC10098338 | biostudies-literature

Osteocalcin biomarker level evaluation on fracture healing with bone defect after stromal vascular fraction application in murine model.

Project description:IntroductionBone defect (3 mm in murine model) is a condition when the bone tissue cannot undergo a natural healing process caused by severe trauma, tumor, or irradiation. A bone defect is a challenge even for experienced Orthopaedic surgeons. Stromal vascular fraction (SVF) is a heterogeneous cell population derived from adipose tissue that results from minimal manipulation of the adipose tissue itself. Several studies have elucidated the effect of either SVF on bone defect healing. However, to the author's knowledge, there is no study evaluating the effect of SVF application on fracture healing, which was measured with osteocalcin biomarker. This study aims to evaluate the effect of SVF application on bone defect healing measured with osteocalcin as a biomarker of bone healing.Materials and methodsThis was an animal study involving twelve Wistar strain Rattus norvegivus. They were divided into three groups: negative group (normal rats), positive group (rats with bone defect and treated without SVF application), and SVF group (rats with bone defect and treated with SVF application). After 30 days, the rats were sacrificed, the osteocalcin biomarkers were evaluated. This biomarker was quantified using ELISA.ResultsOsteocalcin biomarker expressions were higher in the group treated with SVF application than those without using SVF. All comparisons of the SVF group and positive control group showed significant differences (p < 0.05).ConclusionSVF application could aid the healing process in a murine model with bone defect, marked by increased osteocalcin levels.

| S-EPMC8606847 | biostudies-literature

Bone morphogenetic protein-9 is a circulating vascular quiescence factor.

Project description:Angiogenesis is a complex process, requiring a finely tuned balance between numerous stimulatory and inhibitory signals. ALK1 (activin receptor like-kinase 1) is an endothelial-specific type 1 receptor of the transforming growth factor-beta receptor family. Heterozygotes with mutations in the ALK1 gene develop hereditary hemorrhagic telangiectasia type 2 (HHT2). Recently, we reported that bone morphogenetic protein (BMP)9 and BMP10 are specific ligands for ALK1 that potently inhibit microvascular endothelial cell migration and growth. These data lead us to suggest that these factors may play a role in the control of vascular quiescence. To test this hypothesis, we checked their presence in human serum. We found that human serum induced Smad1/5 phosphorylation. To identify the active factor, we tested neutralizing antibodies against BMP members and found that only the anti-BMP9 inhibited serum-induced Smad1/5 phosphorylation. The concentration of circulating BMP9 was found to vary between 2 and 12 ng/mL in sera and plasma from healthy humans, a value well above its EC(50) (50 pg/mL). These data indicated that BMP9 is circulating at a biologically active concentration. We then tested the effects of BMP9 in 2 in vivo angiogenic assays. We found that BMP9 strongly inhibited sprouting angiogenesis in the mouse sponge angiogenesis assay and that BMP9 could inhibit blood circulation in the chicken chorioallantoic membrane assay. Taken together, our results demonstrate that BMP9, circulating under a biologically active form, is a potent antiangiogenic factor that is likely to play a physiological role in the control of adult blood vessel quiescence.

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The half-life of the bone-derived hormone osteocalcin is regulated through O-glycosylation in mice, but not in humans.

Project description:Osteocalcin (OCN) is an osteoblast-derived hormone with pleiotropic physiological functions. Like many peptide hormones, OCN is subjected to post-translational modifications (PTMs) which control its activity. Here, we uncover O-glycosylation as a novel PTM present on mouse OCN and occurring on a single serine (S8) independently of its carboxylation and endoproteolysis, two other PTMs regulating this hormone. We also show that O-glycosylation increases OCN half-life in plasma ex vivo and in the circulation in vivo. Remarkably, in human OCN (hOCN), the residue corresponding to S8 is a tyrosine (Y12), which is not O-glycosylated. Yet, the Y12S mutation is sufficient to O-glycosylate hOCN and to increase its half-life in plasma compared to wildtype hOCN. These findings reveal an important species difference in OCN regulation, which may explain why serum concentrations of OCN are higher in mouse than in human.

| S-EPMC7822592 | biostudies-literature

Undercarboxylated osteocalcin has no adverse effect on endothelial function in rabbit aorta or human vascular cells.

Project description:Undercarboxylated osteocalcin (ucOC) improves glucose metabolism; however, its effects on endothelial cell function are unclear. We examined the biological effect of ucOC on endothelial function in animal models ex vivo and human cells in vitro. Isometric tension and immunohistochemistry techniques were used on the aorta of male New Zealand white rabbits and cell culture techniques were used on human aortic endothelial cells (HAECs) to assess the effect of ucOC in normal and high-glucose environments. Overall, ucOC, both 10 and 30 ng/ml, did not significantly alter acetylcholine-induced blood vessel relaxation in rabbits (p > .05). UcOC treatment did not cause any significant changes in the immunoreactivity of cellular signalling markers (p > .05). In HAEC, ucOC did not change any of the assessed outcomes (p > .05). UcOC has no negative effects on endothelial function which is important to reduce the risks of off target adverse effects if it will be used as a therapeutic option for metabolic disease in the future.

| S-EPMC7891339 | biostudies-literature

Screening and Assessment of Bone Health in Indian Women Using an Indigenous ELISA of Human Osteocalcin a Bone Turnover Marker.

Project description:Osteoporosis a major public health problem of the elderly, is associated with substantial morbidity and socio economic burden. The aim of the study was to screen women with low bone mass using the indigenously developed Osteocalcin (OC) ELISA kit and compare it with commercial ELISA kit and evaluate. The diagnostic potential of the assay was assessed in 359 samples from neighboring tertiary care hospitals over a period of 2 years. OC levels were estimated by the developed indigenous assay in samples, correlated with the Bone Mineral Density (BMD) measurements and compared by a commercial ELISA kit. On the basis of T-scores the women were stratified into Normal and case groups as Osteopenia and Osteoporosis. The serum biochemical parameters calcium and phosphorus were estimated on an auto-analyzer. To compare two different assays Bland-Altman plot and Deming linear regression analysis was performed. The prevalence of Osteopenia was high (56%) and Osteoporosis (13%) in the healthy Indian women aged 21-65 years with significant differences in OC levels in normal and women with low bone mass. Good correlation (p < 0.0001) in the OC levels by the two assays was observed. Cut off limits established earlier with indigenous assay (11.9 ng/mL and 14.9 ng/mL) for Osteopenia and Osteoporosis were similar to those with the commercial kit (13.2 ng/mL and 16.8 ng/mL) respectively. The diagnostic sensitivity, specificity and accuracy of the OC prototype was > 85%. The cost effective OC prototype can be used in screening and management of Indian women with low bone mass.

| S-EPMC7502623 | biostudies-literature

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