The number of patients with osteoporosis and diabetes is rapidly increasing all over the world. Bone is recently recognized as an endocrine organ. Accumulating evidence has shown that osteocalcin, which is specificall...The number of patients with osteoporosis and diabetes is rapidly increasing all over the world. Bone is recently recognized as an endocrine organ. Accumulating evidence has shown that osteocalcin, which is specifically expressed in osteoblasts and secreted into the circulation, regulates glucose homeostasis by stimulating insulin expression in pancreas and adiponectin expression in adipocytes, resulting in improving glucose intolerance. On the other hand, insulin and adiponectin stimulate osteocalcin expression in osteoblasts, suggesting that positive feedforward loops exist among bone, pancreas, and adipose tissue. In addition, recent studies have shown that osteocalcin enhances insulin sensitivity and the differentiation in muscle, while secreted factors from muscle, myokines, regulate bone metabolism. These findings suggest that bone metabolism and glucose metabolism are associated with each other through the action of osteocalcin. In this review, I describe the role of osteocalcin in the interaction among bone, pancreas, brain, adipose tissue, and muscle.展开更多
Genetic studies have revealed a critical role of Distal-homeobox (Dlx) genes in bone formation,and our previous study showed that Dlx2 overexpressing in neural crest cells leads to profound abnormalities of the cranio...Genetic studies have revealed a critical role of Distal-homeobox (Dlx) genes in bone formation,and our previous study showed that Dlx2 overexpressing in neural crest cells leads to profound abnormalities of the craniofacial tissues.The aim of this study was to investigate the role and the underlying molecular mechanisms of Dlx2 in osteogenic differentiation of mouse bone marrow stromal cells (BMSCs) and pre-osteoblast MC3T3-E1 cells.Initially,we observed upregulation of Dlx2 during the early osteogenesis in BMSCs and MC3T3-E1 cells.Moreover,Dlx2 overexpression enhanced alkaline phosphatase (ALP) activity and extracellular matrix mineralization in BMSCs and MC3T3-E1 cell line.In addition,micro-CT of implanted tissues in nude mice confirmed that Dlx2 overexpression in BMSCs promoted bone formation in vivo.Unexpectedly,Dlx2 overexpression had little impact on the expression level of the pivotal osteogenic transcription factors Runx2,Dlx5,Msx2,and Osterix,but led to upregulation of Alp and Osteocalcin (OCN),both of which play critical roles in promoting osteoblast maturation.Importantly,luciferase analysis showed that Dlx2 overexpression stimulated both OCN and Alp promoter activity.Through chromatin-immunoprecipitation assay and site-directed mutagenesis analysis,we provide molecular evidence that Dlx2 transactivates OCN and Alp expression by directly binding to the Dlx2-response cis-acting elements in the promoter of the two genes.Based on these findings,we demonstrate that Dlx2 overexpression enhances osteogenic differentiation in vitro and accelerates bone formation in vivo via direct upregulation of the OCN and Alp gene,suggesting that Dlx2 plays a crucial role in osteogenic differentiation and bone formation.展开更多
AIM To determine a potential relationship between serum undercarboxylated(uc OC) concentration and cardiovascular risk factors in type 2 diabetes(T2D) patients and healthy subjects(HS).METHODS A cross-sectional study ...AIM To determine a potential relationship between serum undercarboxylated(uc OC) concentration and cardiovascular risk factors in type 2 diabetes(T2D) patients and healthy subjects(HS).METHODS A cross-sectional study was conducted on 140 subjects classified into two groups, 70 with T2D and 70 HS. Medical history and physical examination with anthropometric measurements were obtained from all subjects. Body fat percentage was determined by bioelectrical impendency analysis. Serum uc OC concentration was determined by enzyme immunoassay,while serum levels of insulin and hsC RP were obtained using high sensitivity enzyme-linked immunosorbent assay. Insulin resistance was determined using the homeostasis model assessment-IR. Lipid profile [triglycerides,total cholesterol(TC), high-density lipoproteins(HDL-c),low density lipoproteins(LDL-c), very low-density lipoproteins] was determined by spectrophotometry and standard formulas when applicable. RESULTS The T2D patient group showed significantly higher values of waist circumference, waist-to-hip ratio, systolic blood pressure(SBP), diastolic blood pressure(DBP),current smoking, and alcohol use when compared to the HS group(P < 0.05). We observed a significantly lower serum ucO C concentration in T2D than in HS(1.5 ± 1.4vs 2.3 ± 1.8, P < 0.05). In the whole study population,ucO C concentration was inversely correlated with body mass index(BMI)(r =-0.236, P < 0.05), fasting plasma glucose(r =-0.283, P < 0.01) and HDL-c(r =-0.255,P < 0.05); and positively correlated with LDL-c/HDL-c ratio(r = 0.306, P < 0.05) and TC/HDL-c ratio(r =0.284, P < 0.05). In the T2D group, serum uc OC concentration was inversely correlated with BMI(r =-0.310, P < 0.05) and body-fat percentage(r =-0.311,P < 0.05), and positively correlated with DBP(r = 0.450,P < 0.01). In HS group a positive correlation between serum levels of uc OC and SBP(r = 0.277, P < 0.05)was observed. CONCLUSION Serum uc OC is a potential marker for cardiovascular risk in Mexicans because it is related to adiposity parameters, blood pressure and lipid profile.展开更多
BACKGROUND Uncarboxylated osteocalcin(GluOC)has been reported to improve glucose metabolism,prevent type 2 diabetes,and decrease the severity of obesity in mice with type 2 diabetes.GluOC can increase glucose uptake i...BACKGROUND Uncarboxylated osteocalcin(GluOC)has been reported to improve glucose metabolism,prevent type 2 diabetes,and decrease the severity of obesity in mice with type 2 diabetes.GluOC can increase glucose uptake in a variety of cells.Glucose metabolism is the main source of energy for osteoblast proliferation and differentiation.We hypothesized that decarboxylated osteocalcin(dcOC),a kind of GluOC,can increase glucose uptake in MG63 cells(osteoblast-like osteosarcoma cells)and influence their proliferation and differentiation.AIM To investigate the effects of dcOC on glucose uptake in human osteoblast-like osteosarcoma cells and the possible signaling pathways involved.METHODS MG63 cells(human osteoblast-like osteosarcoma cells)were treated with dcOC(0,0.3,3,10,or 30 ng/mL)for 1 and 72 h,and glucose uptake was measured by flow cytometry.The effect of dcOC on cell proliferation was measured with a CCK-8 assay,and alkaline phosphatase(ALP)enzyme activity was measured.PI3K was inhibited with LY294002,and hypoxia-inducible factor 1 alpha(HIF-1α)was silenced with siRNA.Then,GPRC6A(G protein-coupled receptor family C group 6 subtype A),total Akt,phosphorylated Akt,HIF-1α,and glucose transporter 1(GLUT1)levels were measured by Western blot to elucidate the possible pathways by which dcOC modulates glucose uptake.RESULTS The glucose uptake of MG63 cells was significantly increased compared with that of the paired control cells after short-term(1 h)treatment with dcOC at different concentrations(0.3,3,and 10 ng/mL groups,P<0.01;30 ng/mL group,P<0.05).Glucose uptake of MG63 cells was significantly increased compared with that of the paired control cells after long-term(72 h)treatment with dcOC at different concentrations(0.3,3,and 10 ng/mL groups,P<0.01;30 ng/mL group,P<0.05).DcOC triggered Akt phosphorylation in a dose-dependent manner,and the most effective stimulatory concentration of dcOC for short-term(1 h)was 3 ng/mL(P<0.01).LY294002 abolished the dcOC-mediated(1 h)promotion of Akt phosphorylation and glucose uptake without affecting GLUT1 protein expression.Long-term dcOC stimulation triggered Akt phosphorylation and increased the protein levels of HIF-1α,GLUT1,and Runx2 in a dose-dependent manner.Inhibition of HIF-1αwith siRNA abolished the dcOC-mediated glucose uptake and substantially decreased GLUT1 protein expression.DcOC interven-tion promoted cell proliferation in a time-and dose-dependent manner as determined by the CCK-8 assay.Treatment with both 3 ng/mL and 10 ng/mL dcOC affected the ALP activity in MG63 cells after 72 h(P<0.01).CONCLUSION Short-and long-term dcOC treatment can increase glucose uptake and affect proliferation and ALP activity in MG63 cells.This effect may occur through the PI3K/Akt,HIF-1α,and GLUT1 signaling factors.展开更多
文摘The number of patients with osteoporosis and diabetes is rapidly increasing all over the world. Bone is recently recognized as an endocrine organ. Accumulating evidence has shown that osteocalcin, which is specifically expressed in osteoblasts and secreted into the circulation, regulates glucose homeostasis by stimulating insulin expression in pancreas and adiponectin expression in adipocytes, resulting in improving glucose intolerance. On the other hand, insulin and adiponectin stimulate osteocalcin expression in osteoblasts, suggesting that positive feedforward loops exist among bone, pancreas, and adipose tissue. In addition, recent studies have shown that osteocalcin enhances insulin sensitivity and the differentiation in muscle, while secreted factors from muscle, myokines, regulate bone metabolism. These findings suggest that bone metabolism and glucose metabolism are associated with each other through the action of osteocalcin. In this review, I describe the role of osteocalcin in the interaction among bone, pancreas, brain, adipose tissue, and muscle.
基金supported by grant (81771036) from National Natural Science Foundation of China (to S.G.S.)grant (81741028) from National Natural Science Foundation of China (to J.D.)grant (17410710500) Shanghai International Scientific and Technological Cooperation Projects Laser Micromachine and Vascularization of TCP/PCL Scaffolds (to W.Z.)
文摘Genetic studies have revealed a critical role of Distal-homeobox (Dlx) genes in bone formation,and our previous study showed that Dlx2 overexpressing in neural crest cells leads to profound abnormalities of the craniofacial tissues.The aim of this study was to investigate the role and the underlying molecular mechanisms of Dlx2 in osteogenic differentiation of mouse bone marrow stromal cells (BMSCs) and pre-osteoblast MC3T3-E1 cells.Initially,we observed upregulation of Dlx2 during the early osteogenesis in BMSCs and MC3T3-E1 cells.Moreover,Dlx2 overexpression enhanced alkaline phosphatase (ALP) activity and extracellular matrix mineralization in BMSCs and MC3T3-E1 cell line.In addition,micro-CT of implanted tissues in nude mice confirmed that Dlx2 overexpression in BMSCs promoted bone formation in vivo.Unexpectedly,Dlx2 overexpression had little impact on the expression level of the pivotal osteogenic transcription factors Runx2,Dlx5,Msx2,and Osterix,but led to upregulation of Alp and Osteocalcin (OCN),both of which play critical roles in promoting osteoblast maturation.Importantly,luciferase analysis showed that Dlx2 overexpression stimulated both OCN and Alp promoter activity.Through chromatin-immunoprecipitation assay and site-directed mutagenesis analysis,we provide molecular evidence that Dlx2 transactivates OCN and Alp expression by directly binding to the Dlx2-response cis-acting elements in the promoter of the two genes.Based on these findings,we demonstrate that Dlx2 overexpression enhances osteogenic differentiation in vitro and accelerates bone formation in vivo via direct upregulation of the OCN and Alp gene,suggesting that Dlx2 plays a crucial role in osteogenic differentiation and bone formation.
文摘AIM To determine a potential relationship between serum undercarboxylated(uc OC) concentration and cardiovascular risk factors in type 2 diabetes(T2D) patients and healthy subjects(HS).METHODS A cross-sectional study was conducted on 140 subjects classified into two groups, 70 with T2D and 70 HS. Medical history and physical examination with anthropometric measurements were obtained from all subjects. Body fat percentage was determined by bioelectrical impendency analysis. Serum uc OC concentration was determined by enzyme immunoassay,while serum levels of insulin and hsC RP were obtained using high sensitivity enzyme-linked immunosorbent assay. Insulin resistance was determined using the homeostasis model assessment-IR. Lipid profile [triglycerides,total cholesterol(TC), high-density lipoproteins(HDL-c),low density lipoproteins(LDL-c), very low-density lipoproteins] was determined by spectrophotometry and standard formulas when applicable. RESULTS The T2D patient group showed significantly higher values of waist circumference, waist-to-hip ratio, systolic blood pressure(SBP), diastolic blood pressure(DBP),current smoking, and alcohol use when compared to the HS group(P < 0.05). We observed a significantly lower serum ucO C concentration in T2D than in HS(1.5 ± 1.4vs 2.3 ± 1.8, P < 0.05). In the whole study population,ucO C concentration was inversely correlated with body mass index(BMI)(r =-0.236, P < 0.05), fasting plasma glucose(r =-0.283, P < 0.01) and HDL-c(r =-0.255,P < 0.05); and positively correlated with LDL-c/HDL-c ratio(r = 0.306, P < 0.05) and TC/HDL-c ratio(r =0.284, P < 0.05). In the T2D group, serum uc OC concentration was inversely correlated with BMI(r =-0.310, P < 0.05) and body-fat percentage(r =-0.311,P < 0.05), and positively correlated with DBP(r = 0.450,P < 0.01). In HS group a positive correlation between serum levels of uc OC and SBP(r = 0.277, P < 0.05)was observed. CONCLUSION Serum uc OC is a potential marker for cardiovascular risk in Mexicans because it is related to adiposity parameters, blood pressure and lipid profile.
基金Supported by Provincial Science and Technology Department Natural Fund Guidance Project,No.2019-ZD-0774National Natural Science Foundation of China,No.81470998+1 种基金Liaoning Ministry of Education,No.LQNK201715and Liaoning Provincial Doctor Start up Fund,No.20180540008.
文摘BACKGROUND Uncarboxylated osteocalcin(GluOC)has been reported to improve glucose metabolism,prevent type 2 diabetes,and decrease the severity of obesity in mice with type 2 diabetes.GluOC can increase glucose uptake in a variety of cells.Glucose metabolism is the main source of energy for osteoblast proliferation and differentiation.We hypothesized that decarboxylated osteocalcin(dcOC),a kind of GluOC,can increase glucose uptake in MG63 cells(osteoblast-like osteosarcoma cells)and influence their proliferation and differentiation.AIM To investigate the effects of dcOC on glucose uptake in human osteoblast-like osteosarcoma cells and the possible signaling pathways involved.METHODS MG63 cells(human osteoblast-like osteosarcoma cells)were treated with dcOC(0,0.3,3,10,or 30 ng/mL)for 1 and 72 h,and glucose uptake was measured by flow cytometry.The effect of dcOC on cell proliferation was measured with a CCK-8 assay,and alkaline phosphatase(ALP)enzyme activity was measured.PI3K was inhibited with LY294002,and hypoxia-inducible factor 1 alpha(HIF-1α)was silenced with siRNA.Then,GPRC6A(G protein-coupled receptor family C group 6 subtype A),total Akt,phosphorylated Akt,HIF-1α,and glucose transporter 1(GLUT1)levels were measured by Western blot to elucidate the possible pathways by which dcOC modulates glucose uptake.RESULTS The glucose uptake of MG63 cells was significantly increased compared with that of the paired control cells after short-term(1 h)treatment with dcOC at different concentrations(0.3,3,and 10 ng/mL groups,P<0.01;30 ng/mL group,P<0.05).Glucose uptake of MG63 cells was significantly increased compared with that of the paired control cells after long-term(72 h)treatment with dcOC at different concentrations(0.3,3,and 10 ng/mL groups,P<0.01;30 ng/mL group,P<0.05).DcOC triggered Akt phosphorylation in a dose-dependent manner,and the most effective stimulatory concentration of dcOC for short-term(1 h)was 3 ng/mL(P<0.01).LY294002 abolished the dcOC-mediated(1 h)promotion of Akt phosphorylation and glucose uptake without affecting GLUT1 protein expression.Long-term dcOC stimulation triggered Akt phosphorylation and increased the protein levels of HIF-1α,GLUT1,and Runx2 in a dose-dependent manner.Inhibition of HIF-1αwith siRNA abolished the dcOC-mediated glucose uptake and substantially decreased GLUT1 protein expression.DcOC interven-tion promoted cell proliferation in a time-and dose-dependent manner as determined by the CCK-8 assay.Treatment with both 3 ng/mL and 10 ng/mL dcOC affected the ALP activity in MG63 cells after 72 h(P<0.01).CONCLUSION Short-and long-term dcOC treatment can increase glucose uptake and affect proliferation and ALP activity in MG63 cells.This effect may occur through the PI3K/Akt,HIF-1α,and GLUT1 signaling factors.
