Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures...Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-la （HIF-la） in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-la mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-la and FGF23 were co-localized in spindle- shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-la protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-la expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-la inhibitors decreased HIF-la and FGF23 protein accumulation and inhibited HIF-la-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-la consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-la inhibitor. These results show for the first time that HIF-la is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-la activity in TIO contributes to the aberrant FGF23 production in these patients.展开更多
BACKGROUND The incidence and prevalence of atrial fibrillation are increasing each year,and this condition is one of the most common clinical arrhythmias.AIM To investigate the levels and significance of serum fibrobl...BACKGROUND The incidence and prevalence of atrial fibrillation are increasing each year,and this condition is one of the most common clinical arrhythmias.AIM To investigate the levels and significance of serum fibroblast growth factor 23(FGF-23)and miR-208 b in patients with atrial fibrillation and their relationship with prognosis.METHODS From May 2018 to October 2019,240 patients with atrial fibrillation were selected as an observation group,including 134 with paroxysmal atrial fibrillation and 106 with persistent atrial fibrillation;150 patients with healthy sinus rhythm were selected as a control group.The serum levels of FGF-23 and miR-208 b in the two groups were measured.In the observation group,cardiac parameters were determined by echocardiography.RESULTS The serum levels of FGF-23 and miR-208 b in the observation group were 210.20±89.60 ng/mL and 5.30±1.22 ng/mL,which were significantly higher than the corresponding values in the control group(P<0.05).In the observation group,the serum levels of FGF-23 and miR-208 b in patients with persistent atrial fibrillation were 234.22±70.05 ng/mL and 5.83±1.00 ng/mL,which were significantly higher than the corresponding values in patients with paroxysmal atrial fibrillation(P<0.05).The left atrial dimension(LAD)of patients with persistent atrial fibrillation was 38.81±5.11 mm,which was significantly higher than that of patients with paroxysmal atrial fibrillation(P>0.05).The serum levels of FGF-23and miR-208 b were positively correlated with the LAD(r=0.411 and 0.382,P<0.05).In the observation group,the serum levels of FGF-23 and miR-208 b in patients with a major cardiovascular event(MACE)were 243.30±72.29 ng/mL and 6.12±1.12 ng/mL,which were significantly higher than the corresponding values in patients without a MACE(P<0.05).CONCLUSION The serum levels of FGF-23 and miR-208 b are increased in patients with atrial fibrillation and are related to the type of disease,cardiac parameters,and prognosis.展开更多
Objective:To explore the levels of fibroblast growth factor 23(FGF23)during pregnancy and its relationship with intrauterine growth restriction(IUGR).Methods:Pregnant rats were classified into an ad libitum rat chow g...Objective:To explore the levels of fibroblast growth factor 23(FGF23)during pregnancy and its relationship with intrauterine growth restriction(IUGR).Methods:Pregnant rats were classified into an ad libitum rat chow group(ad libitum rat chow,AD group,n=25)and an undernutrition group(50%of their daily food requirement,UN group,n=25).The levels of maternal serum FGF23,tissue homogenate FGF23,and bone gla protein in fetal rats,and placental FGF23 mRNA and protein expression were examined by enzyme-linked immunosorbent assay,real-time qPCR analysis respectively.Finally,the effect of recombinant FGF23 on the viability of MG-63 cells was determined by cell proliferation assay.Data were analyzed with independent two-tailed t test and one-way analysis of variance.Spearman rank-order correlation coefficients(continuous variables)was performed to determine the relationship of results.Results:The diet restriction induced IUGR in rat offsprings,and the UN group exhibited a significantly lower FGF23 level(P<0.05,n=5).The FGF23 level was increased and peaked in maternal serum on gestation day(GD)15,but peaked in fetal and placenta on GD20.Moreover,the tissue homogenate levels of FGF23 and bone gla protein in fetal rats in both groups were positively correlated(r=0.923,P<0.05;r=0.925,P<0.05,respectively,n=15),FGF23 was localized to both decidual and labyrinth zones,with remarkably higher expression on GD20,P<0.05,n=5.In vitro,recombinant human FGF23 enhanced MG-63 cell viability,P<0.05,n=5.Conclusion:Prenatal undernutrition could decrease the FGF23 expression in fetal rats caused by the mother through the placenta,and induced the IUGR and hindered the ossification.And the FGF23 levels are peaked on GD15 mother but peaked on GD20 placenta and fetuses,these might be associated with the over compensation of maternal placenta on GD20.展开更多
Recently,fibroblast growth factor 23(FGF23)has sparked widespread interest because of its potential role in regulating phosphate and vitamin D metabolism.In this review,we summarized the FGF superfamily,the mechanism ...Recently,fibroblast growth factor 23(FGF23)has sparked widespread interest because of its potential role in regulating phosphate and vitamin D metabolism.In this review,we summarized the FGF superfamily,the mechanism of FGF23 on phosphate and vitamin D metabolism,and the FGF23 related bone disease.展开更多
Oncogenic osteomalacia (OOM) is an uncommon metabolic and bone disease caused by fibroblast growth factor 23 (FGF23), a phosphaturic factor produced by phosphaturic mesenchymal tumors (mixed connective tissue variant,...Oncogenic osteomalacia (OOM) is an uncommon metabolic and bone disease caused by fibroblast growth factor 23 (FGF23), a phosphaturic factor produced by phosphaturic mesenchymal tumors (mixed connective tissue variant, PMTMCTV) characterized by phosphate leakage from kidneys and subsequent hypophosphatemia. In this paper, we present the case of a patient, 42-year-old woman affected by left side limp and pain involving lumbar spine, pelvis and hip joints, referred to the Rheumatology Department of our Hospital for the treatment of a suspected sero-negative spondilo-arthritis. During hospitalization patient began an immuno-suppressive therapy with TNF-alpha inhibitors associated with Pamidornate, Indometacin, Esomeprazole and vitamin D3. Nevertheless pain did not decrease and a new examination found a worst hypophosphatemia (1 mg/dl) with normal Ca and PTH’s plasma values. During the same check-up a painful bulge on the anterior part of the right knee was observed and the Magnetic Resonance Imaging scan revealed an ovular solid lesion in the soft tissue closed to the upper part of the patella. Histological analysis identified the lesion as a PMTMCTV. After surgical removal patient got complete recovery. We will discuss about diagnostic evaluation, differential diagnosis and treatment.展开更多
基金supported by NIH grants AR049510 (TLC) and AR045955 (LDQ)
文摘Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-la （HIF-la） in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-la mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-la and FGF23 were co-localized in spindle- shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-la protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-la expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-la inhibitors decreased HIF-la and FGF23 protein accumulation and inhibited HIF-la-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-la consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-la inhibitor. These results show for the first time that HIF-la is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-la activity in TIO contributes to the aberrant FGF23 production in these patients.
文摘BACKGROUND The incidence and prevalence of atrial fibrillation are increasing each year,and this condition is one of the most common clinical arrhythmias.AIM To investigate the levels and significance of serum fibroblast growth factor 23(FGF-23)and miR-208 b in patients with atrial fibrillation and their relationship with prognosis.METHODS From May 2018 to October 2019,240 patients with atrial fibrillation were selected as an observation group,including 134 with paroxysmal atrial fibrillation and 106 with persistent atrial fibrillation;150 patients with healthy sinus rhythm were selected as a control group.The serum levels of FGF-23 and miR-208 b in the two groups were measured.In the observation group,cardiac parameters were determined by echocardiography.RESULTS The serum levels of FGF-23 and miR-208 b in the observation group were 210.20±89.60 ng/mL and 5.30±1.22 ng/mL,which were significantly higher than the corresponding values in the control group(P<0.05).In the observation group,the serum levels of FGF-23 and miR-208 b in patients with persistent atrial fibrillation were 234.22±70.05 ng/mL and 5.83±1.00 ng/mL,which were significantly higher than the corresponding values in patients with paroxysmal atrial fibrillation(P<0.05).The left atrial dimension(LAD)of patients with persistent atrial fibrillation was 38.81±5.11 mm,which was significantly higher than that of patients with paroxysmal atrial fibrillation(P>0.05).The serum levels of FGF-23and miR-208 b were positively correlated with the LAD(r=0.411 and 0.382,P<0.05).In the observation group,the serum levels of FGF-23 and miR-208 b in patients with a major cardiovascular event(MACE)were 243.30±72.29 ng/mL and 6.12±1.12 ng/mL,which were significantly higher than the corresponding values in patients without a MACE(P<0.05).CONCLUSION The serum levels of FGF-23 and miR-208 b are increased in patients with atrial fibrillation and are related to the type of disease,cardiac parameters,and prognosis.
基金This work was supported by the National Natural Science Foundation of China(No.81571465,No.81871175)
文摘Objective:To explore the levels of fibroblast growth factor 23(FGF23)during pregnancy and its relationship with intrauterine growth restriction(IUGR).Methods:Pregnant rats were classified into an ad libitum rat chow group(ad libitum rat chow,AD group,n=25)and an undernutrition group(50%of their daily food requirement,UN group,n=25).The levels of maternal serum FGF23,tissue homogenate FGF23,and bone gla protein in fetal rats,and placental FGF23 mRNA and protein expression were examined by enzyme-linked immunosorbent assay,real-time qPCR analysis respectively.Finally,the effect of recombinant FGF23 on the viability of MG-63 cells was determined by cell proliferation assay.Data were analyzed with independent two-tailed t test and one-way analysis of variance.Spearman rank-order correlation coefficients(continuous variables)was performed to determine the relationship of results.Results:The diet restriction induced IUGR in rat offsprings,and the UN group exhibited a significantly lower FGF23 level(P<0.05,n=5).The FGF23 level was increased and peaked in maternal serum on gestation day(GD)15,but peaked in fetal and placenta on GD20.Moreover,the tissue homogenate levels of FGF23 and bone gla protein in fetal rats in both groups were positively correlated(r=0.923,P<0.05;r=0.925,P<0.05,respectively,n=15),FGF23 was localized to both decidual and labyrinth zones,with remarkably higher expression on GD20,P<0.05,n=5.In vitro,recombinant human FGF23 enhanced MG-63 cell viability,P<0.05,n=5.Conclusion:Prenatal undernutrition could decrease the FGF23 expression in fetal rats caused by the mother through the placenta,and induced the IUGR and hindered the ossification.And the FGF23 levels are peaked on GD15 mother but peaked on GD20 placenta and fetuses,these might be associated with the over compensation of maternal placenta on GD20.
文摘Recently,fibroblast growth factor 23(FGF23)has sparked widespread interest because of its potential role in regulating phosphate and vitamin D metabolism.In this review,we summarized the FGF superfamily,the mechanism of FGF23 on phosphate and vitamin D metabolism,and the FGF23 related bone disease.
文摘Oncogenic osteomalacia (OOM) is an uncommon metabolic and bone disease caused by fibroblast growth factor 23 (FGF23), a phosphaturic factor produced by phosphaturic mesenchymal tumors (mixed connective tissue variant, PMTMCTV) characterized by phosphate leakage from kidneys and subsequent hypophosphatemia. In this paper, we present the case of a patient, 42-year-old woman affected by left side limp and pain involving lumbar spine, pelvis and hip joints, referred to the Rheumatology Department of our Hospital for the treatment of a suspected sero-negative spondilo-arthritis. During hospitalization patient began an immuno-suppressive therapy with TNF-alpha inhibitors associated with Pamidornate, Indometacin, Esomeprazole and vitamin D3. Nevertheless pain did not decrease and a new examination found a worst hypophosphatemia (1 mg/dl) with normal Ca and PTH’s plasma values. During the same check-up a painful bulge on the anterior part of the right knee was observed and the Magnetic Resonance Imaging scan revealed an ovular solid lesion in the soft tissue closed to the upper part of the patella. Histological analysis identified the lesion as a PMTMCTV. After surgical removal patient got complete recovery. We will discuss about diagnostic evaluation, differential diagnosis and treatment.
