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
Fibroblast growth factor 23 （FGF23） is a hormone that is mainly secreted by osteocytes and osteoblasts in bone. The critical role of FGF23 in mineral ion homeostasis was first identified in human genetic and acquire...Fibroblast growth factor 23 （FGF23） is a hormone that is mainly secreted by osteocytes and osteoblasts in bone. The critical role of FGF23 in mineral ion homeostasis was first identified in human genetic and acquired rachitic diseases and has been further characterised in animal models. Recent studies have revealed that the levels of FGF23 increase significantly at the very early stages of chronic kidney disease （CKD） and may play a critical role in mineral ion disorders and bone metabolism in these patients. Our recent publications have also shown that FGF23 and its cofactor, Klotho, may play an independent role in directly regulating bone mineralisation instead of producing a systematic effect. In this review, we will discuss the new role of FGF23 in bone mineralisation and the pathophysiology of CKD-related bone disorders.展开更多
Tumor-induced osteomalacia (TIO), or oncogenic osteomalacia (OOM), is a rare acquired paraneoplastic disease characterized by renal phosphate wasting and hypophosphatemia. Recent evidence shows that tumor-overexpresse...Tumor-induced osteomalacia (TIO), or oncogenic osteomalacia (OOM), is a rare acquired paraneoplastic disease characterized by renal phosphate wasting and hypophosphatemia. Recent evidence shows that tumor-overexpressed fibroblast growth factor 23 (FGF23) is responsible for the hypophosphatemia and osteomalacia. The tumors associated with TIO are usually phosphaturic mesenchymal tumor mixed connective tissue variants (PMTMCT). Surgical removal of the responsible tumors is clinically essential for the treatment of TIO. However, identifying the responsible tumors is often difficult. Here, we report a case of a TIO patient with elevated serum FGF23 levels suffering from bone pain and hypophosphatemia for more than three years. A tumor was finally located in first metacarpal bone by octreotide scintigraphy and she was cured by surgery. After complete excision of the tumor, serum FGF23 levels rapidly decreased, dropping to 54.7% of the preoperative level one hour after surgery and eventually to a little below normal. The patient's serum phosphate level rapidly improved and returned to normal level in four days. Accordingly, her clinical symptoms were greatly improved within one month after surgery. There was no sign of tumor recurrence during an 18-month period of follow-up. According to pathology, the tumor was originally diagnosed as "glomangioma" based upon a biopsy sample, "proliferative giant cell tumor of tendon sheath" based upon sections of tumor, and finally diagnosed as PMTMCT by consultation one year after surgery. In conclusion, although an extremely rare disease, clinicians and pathologists should be aware of the existence of TIO and PMTMCT, respectively.展开更多
Background: Left ventricular hypertrophy (LVH) is a common cardiovascular complication and an independent risk factor for cardiovascular death in hemodialysis (HD) patients. Previous studies have shown that fibroblast...Background: Left ventricular hypertrophy (LVH) is a common cardiovascular complication and an independent risk factor for cardiovascular death in hemodialysis (HD) patients. Previous studies have shown that fibroblast growth factor 23 (FGF23), which has an important role in phosphate metabolism, is elevated in HD patients. Objectives: The aim of this study was to determine the association of FGF23 and LVH and the prognostic value of serum FGF23 level in HD patients. One hundred seven HD patients were evaluated for LVH by echocardiography. Serum FGF23 levels were measured using a commercial enzyme-linked immunosorbent assay kit. Results: Patients with LVH were more likely to have higher systolic blood pressure (BP) and LVH was significantly associated with female gender and higher serum levels of phosphate and calcium ×phosphate products. LVH was also associated with higher serum FGF23 level. Multivariate analysis indicated that serum FGF23 level, systolic BP, and serum phosphate level remained correlated with LVH. This suggested that serum FGF23 level is independently associated with LVH in our HD patients. Cox analysis indicated no significant difference in risk of death for patients with elevated serum FGF23 level. Conclusion: LVH has a high prevalence in HD patients, and FGF23 is independently associated with LVH but is not a predictor for prognosis during a 4-year follow-up period.展开更多
Background Hypophosphatemic rickets/osteomalacia is a group of diseases characterised by defective mineralization of bone due to hypophosphatemia and low 1,25-dihydroxy vitamin D. To explore the role of fibroblast gro...Background Hypophosphatemic rickets/osteomalacia is a group of diseases characterised by defective mineralization of bone due to hypophosphatemia and low 1,25-dihydroxy vitamin D. To explore the role of fibroblast growth factor 23 （FGF-23） in the regulation of phosphate homeostasis, we measured the circulating concentrations of this growth factor in healthy individuals and in patients with hypophosphatemic rickets/osteomalacia. Methods Nineteen patients with hypophosphatemic rickets/osteomalacia were included in hypophosphatemic group （HP, 12 female and 7 male, mean age was 30 years）, and 19 healthy age-matched individuals served as the control group. Full length FGF-23 fragments were measured by two-site enzyme-linked immunosorbent assay.Results Mean FGF-23 concentrations were significantly higher in the HP group （（87.4±43.6） pg/ml） compared with the control group （（19.2±6.16） pg/ml; P 〈0.001）. In 1 patient with tumour-induced osteomalacia, serum FGF-23 concentrations were 84.1 pg/ml; these concentrations were normalized 2 hours after a hemangiopericytoma resection （7.8 pg/ml）. Subsequently, serum 1,25（OH）2 vitamin D3 concentrations significantly increased from 21.3 pg/ml to 89.3 pg/ml, and serum phosphorus levels were normalized. Conclusions Serum FGF-23 concentrations were markedly elevated in patients with hypophosphatemic rickets. FGF-23 plays an important role in the pathogenesis of hypophosphatemic rickets/osteomalacia.展开更多
The present study was carried out to evaluate the effect of dietary supplemental vitamin D_(3) on fibroblast growth factor 23(FGF23)signals as well as phosphorus homeostasis and metabolism in laying hens.Fourteen 40-w...The present study was carried out to evaluate the effect of dietary supplemental vitamin D_(3) on fibroblast growth factor 23(FGF23)signals as well as phosphorus homeostasis and metabolism in laying hens.Fourteen 40-week-old Hy-Line Brown layers were randomly assigned into 2 treatments:1)vitamin D_(3) restriction group(n=7)fed 0 IU/kg vitamin D_(3) diet,and 2)regular vitamin D_(3) group(n=7)fed 1,600 IU/kg vitamin D_(3) diet.The study lasted for 21 d.Serum parameters,phosphorus and calcium excretion status,and tissue expressions of type II sodium-phosphate co-transporters(NPt2),FGF23 signals and vitamin D_(3) metabolic regulators were determined.Hens fed the vitamin D_(3) restricted diet had decreased serum phosphorus levels(by 31.3%,P=0.028)when compared to those fed regular vitamin D_(3) diet.In response to the decreased serum phosphorus,the vitamin D_(3) restricted laying hens exhibited:1)suppressed kidney expressions of 25-hydroxyvitamin D 1-a-hydroxylase(CYP27B1,by 52.8%,P=0.036)and 1,25-dihydroxyvitamin D 24-hydroxylase(CYP24A1,by 99.4%,P=0.032);2)suppressed serum levels of FGF23(by 14.6%,P=0.048)and increased serum alkaline phosphatase level(by 414.1%,P=0.012);3)decreased calvaria mRNA expressions of fibroblast growth factor receptors(FGFR1,by 85.2%,P=0.003,FGFR2,by 89.4%,P=0.014,FGFR3,by 88.8%,P=0.017,FGFR4,by 89.6%,P=0.030);4)decreased kidney mRNA expressions of FGFR1(by 65.5%,P=0.021),FGFR4(by 66.0%,P=0.050)and KLOTHO(by 68.8%,P=0.038);5)decreased kidney protein expression of type 2a sodium-phosphorus co-transporters(by 54.3%,P=0.039);and 6)increased percent excreta calcium(by 26.9%,P=0.002).In conclusion,the deprivation of dietary vitamin D_(3) decreased FGF23 signals in laying hens by reducing serum FGF23 level and suppressing calvaria and kidney mRNA expressions of FGF23 receptors.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.
基金supported by the National Natural Science Foundation of China (81371173)the Program for New Century Excellent Talents in University (NCET-12-0379)+1 种基金Sichuan Provincial Government Grant (2013JQ0017)supported by Open Fund of State Key Laboratory of Oral Diseases, Sichuan University
文摘Fibroblast growth factor 23 （FGF23） is a hormone that is mainly secreted by osteocytes and osteoblasts in bone. The critical role of FGF23 in mineral ion homeostasis was first identified in human genetic and acquired rachitic diseases and has been further characterised in animal models. Recent studies have revealed that the levels of FGF23 increase significantly at the very early stages of chronic kidney disease （CKD） and may play a critical role in mineral ion disorders and bone metabolism in these patients. Our recent publications have also shown that FGF23 and its cofactor, Klotho, may play an independent role in directly regulating bone mineralisation instead of producing a systematic effect. In this review, we will discuss the new role of FGF23 in bone mineralisation and the pathophysiology of CKD-related bone disorders.
文摘Tumor-induced osteomalacia (TIO), or oncogenic osteomalacia (OOM), is a rare acquired paraneoplastic disease characterized by renal phosphate wasting and hypophosphatemia. Recent evidence shows that tumor-overexpressed fibroblast growth factor 23 (FGF23) is responsible for the hypophosphatemia and osteomalacia. The tumors associated with TIO are usually phosphaturic mesenchymal tumor mixed connective tissue variants (PMTMCT). Surgical removal of the responsible tumors is clinically essential for the treatment of TIO. However, identifying the responsible tumors is often difficult. Here, we report a case of a TIO patient with elevated serum FGF23 levels suffering from bone pain and hypophosphatemia for more than three years. A tumor was finally located in first metacarpal bone by octreotide scintigraphy and she was cured by surgery. After complete excision of the tumor, serum FGF23 levels rapidly decreased, dropping to 54.7% of the preoperative level one hour after surgery and eventually to a little below normal. The patient's serum phosphate level rapidly improved and returned to normal level in four days. Accordingly, her clinical symptoms were greatly improved within one month after surgery. There was no sign of tumor recurrence during an 18-month period of follow-up. According to pathology, the tumor was originally diagnosed as "glomangioma" based upon a biopsy sample, "proliferative giant cell tumor of tendon sheath" based upon sections of tumor, and finally diagnosed as PMTMCT by consultation one year after surgery. In conclusion, although an extremely rare disease, clinicians and pathologists should be aware of the existence of TIO and PMTMCT, respectively.
文摘Background: Left ventricular hypertrophy (LVH) is a common cardiovascular complication and an independent risk factor for cardiovascular death in hemodialysis (HD) patients. Previous studies have shown that fibroblast growth factor 23 (FGF23), which has an important role in phosphate metabolism, is elevated in HD patients. Objectives: The aim of this study was to determine the association of FGF23 and LVH and the prognostic value of serum FGF23 level in HD patients. One hundred seven HD patients were evaluated for LVH by echocardiography. Serum FGF23 levels were measured using a commercial enzyme-linked immunosorbent assay kit. Results: Patients with LVH were more likely to have higher systolic blood pressure (BP) and LVH was significantly associated with female gender and higher serum levels of phosphate and calcium ×phosphate products. LVH was also associated with higher serum FGF23 level. Multivariate analysis indicated that serum FGF23 level, systolic BP, and serum phosphate level remained correlated with LVH. This suggested that serum FGF23 level is independently associated with LVH in our HD patients. Cox analysis indicated no significant difference in risk of death for patients with elevated serum FGF23 level. Conclusion: LVH has a high prevalence in HD patients, and FGF23 is independently associated with LVH but is not a predictor for prognosis during a 4-year follow-up period.
基金This study was supported by National Natural Science Foundation of China （NSFC） （No. 30370781） and Doctoral Fund of Ministry of Education of China （No. 20040023055） The authors state that there are no conflicts of interest in this study.
文摘Background Hypophosphatemic rickets/osteomalacia is a group of diseases characterised by defective mineralization of bone due to hypophosphatemia and low 1,25-dihydroxy vitamin D. To explore the role of fibroblast growth factor 23 （FGF-23） in the regulation of phosphate homeostasis, we measured the circulating concentrations of this growth factor in healthy individuals and in patients with hypophosphatemic rickets/osteomalacia. Methods Nineteen patients with hypophosphatemic rickets/osteomalacia were included in hypophosphatemic group （HP, 12 female and 7 male, mean age was 30 years）, and 19 healthy age-matched individuals served as the control group. Full length FGF-23 fragments were measured by two-site enzyme-linked immunosorbent assay.Results Mean FGF-23 concentrations were significantly higher in the HP group （（87.4±43.6） pg/ml） compared with the control group （（19.2±6.16） pg/ml; P 〈0.001）. In 1 patient with tumour-induced osteomalacia, serum FGF-23 concentrations were 84.1 pg/ml; these concentrations were normalized 2 hours after a hemangiopericytoma resection （7.8 pg/ml）. Subsequently, serum 1,25（OH）2 vitamin D3 concentrations significantly increased from 21.3 pg/ml to 89.3 pg/ml, and serum phosphorus levels were normalized. Conclusions Serum FGF-23 concentrations were markedly elevated in patients with hypophosphatemic rickets. FGF-23 plays an important role in the pathogenesis of hypophosphatemic rickets/osteomalacia.
基金the National Natural Science Foundation of China(31902175)Shaanxi Provincial Key Research and Development Program(2019NY-077)+1 种基金Shaanxi Feed Engineering Technology Research Center(2019HBGC-16)the Program for Shaanxi Science&Technology from Shaanxi Provincial Science and Technology Department(2021TD-30).
文摘The present study was carried out to evaluate the effect of dietary supplemental vitamin D_(3) on fibroblast growth factor 23(FGF23)signals as well as phosphorus homeostasis and metabolism in laying hens.Fourteen 40-week-old Hy-Line Brown layers were randomly assigned into 2 treatments:1)vitamin D_(3) restriction group(n=7)fed 0 IU/kg vitamin D_(3) diet,and 2)regular vitamin D_(3) group(n=7)fed 1,600 IU/kg vitamin D_(3) diet.The study lasted for 21 d.Serum parameters,phosphorus and calcium excretion status,and tissue expressions of type II sodium-phosphate co-transporters(NPt2),FGF23 signals and vitamin D_(3) metabolic regulators were determined.Hens fed the vitamin D_(3) restricted diet had decreased serum phosphorus levels(by 31.3%,P=0.028)when compared to those fed regular vitamin D_(3) diet.In response to the decreased serum phosphorus,the vitamin D_(3) restricted laying hens exhibited:1)suppressed kidney expressions of 25-hydroxyvitamin D 1-a-hydroxylase(CYP27B1,by 52.8%,P=0.036)and 1,25-dihydroxyvitamin D 24-hydroxylase(CYP24A1,by 99.4%,P=0.032);2)suppressed serum levels of FGF23(by 14.6%,P=0.048)and increased serum alkaline phosphatase level(by 414.1%,P=0.012);3)decreased calvaria mRNA expressions of fibroblast growth factor receptors(FGFR1,by 85.2%,P=0.003,FGFR2,by 89.4%,P=0.014,FGFR3,by 88.8%,P=0.017,FGFR4,by 89.6%,P=0.030);4)decreased kidney mRNA expressions of FGFR1(by 65.5%,P=0.021),FGFR4(by 66.0%,P=0.050)and KLOTHO(by 68.8%,P=0.038);5)decreased kidney protein expression of type 2a sodium-phosphorus co-transporters(by 54.3%,P=0.039);and 6)increased percent excreta calcium(by 26.9%,P=0.002).In conclusion,the deprivation of dietary vitamin D_(3) decreased FGF23 signals in laying hens by reducing serum FGF23 level and suppressing calvaria and kidney mRNA expressions of FGF23 receptors.
文摘成纤维细胞生长因子23(fibroblast growth factor 23,FGF23)是骨细胞和成骨细胞来源的一种内分泌型信号蛋白,可通过成纤维细胞生长因子受体/α-Klotho复合物调节体内的血清磷酸盐和1,25-二羟维生素D水平,维持体内磷酸盐动态平衡。由于FGF23对骨矿物质稳态发挥了关键作用,其对慢性肾脏病的矿物质和骨代谢异常(chronic kidney disease-mineral and bone disorder,CKD-MBD)的影响及作用机制受到了研究人员的广泛关注。研究证实,FGF23通过直接或间接途径参与了骨矿物质的形成和骨代谢,对骨微结构和骨密度的改变有重要影响。目前,围绕FGF23进行治疗CKD-MBD的新药研究进展缓慢。中药因其治疗CKD-MBD疗效确切且价格低廉,已在临床广泛应用。近年来,研究人员对中药靶向调控FGF23治疗CKD-MBD进行了深入研究。笔者整理及分析了国内外近年来的相关文献,阐释了FGF23在CKD-MBD中的作用,并综述了中药靶向调控FGF23治疗CKD-MBD的研究进展,以期为临床应用中药治疗CKD-MBD提供新思路和理论基础。
