The klotho gene has been identified as an aging suppressor that encodes a protein involved in cardiovascular disease （CVD）. The inac- tivation of the klotho gene causes serious systemic disorders resembling human ag...The klotho gene has been identified as an aging suppressor that encodes a protein involved in cardiovascular disease （CVD）. The inac- tivation of the klotho gene causes serious systemic disorders resembling human aging, such as atherosderosis, diffuse vascular calcification and shortened life span. Klotho has been demonstrated to ameliorate vascular endothelial dysfunction and delay vascular calcification. Fur- thermore, klotho gene polymorphisms in the human are associated with various cardiovascular events. Recent experiments show that klotho may reduce transient receptor potential canonical6 （TRPC6） channels, resulting in protecting the heart from hypertrophy and systolic dys- function. Fibroblast growth factor23 （FGF23） is a bone-derived hormone that plays an important role in the regulation of phosphate and vi- tamin D metabolism. FGF23 accelerates urinary phosphate excretion and suppresses 1,25-dihydroxy vitaminD3 （1,25（OH）2D3）synthesis in the presence ofFGF receptorl （FGFR1） and its co-receptor ldotho, principally in the kidney. The hormonal affects of circulating klotho pro- tein and FGF23 on vascular and heart have contributed to an understanding of their roles in the pathophysiology of arterial stiffness and left ventricular hypertrophy. Klotho and FGF23 appear to play a critical role in the pathogenesis of vascular disease, and may represent a novel potential therapeutic strategy for clinical intervention.展开更多
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
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
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
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
目的观察血清成纤维生长因子-23(fibroblast growth factor 23,FGF23)/抗衰老基因Klotho、辅助性T淋巴细胞(helper T lymphocytes,Th)1/Th2细胞因子在老年终末期肾病患者中的表达,并分析对医院感染的预测和预后的影响。方法选取2021年1...目的观察血清成纤维生长因子-23(fibroblast growth factor 23,FGF23)/抗衰老基因Klotho、辅助性T淋巴细胞(helper T lymphocytes,Th)1/Th2细胞因子在老年终末期肾病患者中的表达,并分析对医院感染的预测和预后的影响。方法选取2021年1月1日至2022年12月31日自贡市精神卫生中心(自贡市老年病医院)收治的106例老年终末期肾病患者,男65例,年龄范围60~84岁,年龄(67.21±3.07)岁,女41例,年龄范围60~84岁,年龄(67.65±2.98)岁,于入院第2天检测血清FGF23、抗衰老基因Klotho、Th1细胞因子[γ干扰素(interferon-γ,IFN-γ)、白介素2(interleukin-2,IL-2)]、Th2细胞因子(IL-4、IL-10)水平,进行急性生理功能及慢性健康状况评分Ⅱ(acute physiology and chronic health status scoring systemⅡ,APACHEⅡ)评估。根据住院期间是否发生医院感染分为感染组(28例)、未感染组(78例),比较两组各项血清指标及APACHEⅡ评分水平,分析各项指标与APACHEⅡ评分的相关性。随访3个月统计患者生存预后[生存(71例)、死亡(35例)],比较不同预后患者血清FGF23、Klotho、IFN-γ、IL-2、IL-4、IL-10水平,分析各项指标对医院感染及预后的预测价值及临床效用。结果106例老年终末期肾病患者根据住院期间是否发生医院感染分为感染组(28例)、未感染组(78例),随访3个月后生存71例、死亡35例。入院第2天感染组血清FGF23、IL-4、IL-10水平及APACHEⅡ评分分别为(78.64±20.16)ng/mL、(20.14±1.48)μg/L、(22.47±2.56)μg/L、(26.38±6.51)分,未感染组分别为(60.17±16.83)ng/mL、(16.25±1.21)μg/L、(19.52±1.86)μg/L、(22.97±6.45)分,感染组血清FGF23、IL-4、IL-10水平及APACHEⅡ评分均高于未感染组(P<0.05);入院第2天感染组血清Klotho、IFN-γ、IL-2水平分别为(34.95±12.62)ng/mL、(22.19±1.69)μg/L、(28.73±2.95)μg/L,未感染组分别为(51.61±16.08)ng/mL、(25.31±1.74)μg/L、(33.95±1.52)μg/L,感染组血清Klotho、IFN-γ、IL-2水平均低于未感染组(P<0.05);血清FGF23、IL-4、IL-10水平与APACHEⅡ评分呈正相关(相关系数r=0.629、0.597、0.612,P均<0.05),血清Klotho、IFN-γ、IL-2水平与APACHEⅡ评分呈负相关(相关系数r=-0.632、-0.718、-0.701、0.597,P均<0.05);死亡患者入组后1个月血清FGF23、IL-10、IL-4水平分别为(77.49±21.85)ng/mL、(24.76±4.77)μg/L、(24.81±6.28)μg/L,生存患者分别为(58.92±16.94)ng/mL、(18.10±3.82)μg/L、(13.57±4.38)μg/L,死亡患者入组后1个月血清FGF23、IL-10、IL-4水平高于生存患者(P<0.05);死亡患者入组后1个月血清Klotho、IFN-γ、IL-2水平分别为(30.03±11.76)ng/mL、(20.33±2.63)μg/L、(27.19±4.91)μg/L,生存患者分别为(55.68±17.02)ng/mL、(26.54±4.79)μg/L、(35.22±5.64)μg/L,死亡患者入组后1个月血清Klotho、IFN-γ、IL-2水平低于生存患者(P<0.05);血清FGF23、Klotho、IFN-γ、IL-2、IL-4、IL-10预测终末期老年肾病患者发生医院感染、生存预后曲线下面积分别为0.904(OR:0.832~0.953)、0.911(OR:0.840~0.958),且具有良好临床效用(P<0.05)。结论老年终末期肾病患者血清FGF23/Klotho、Th1/Th2细胞因子水平失衡,合并感染患者血清FGF23、IL-10、IL-4水平异常升高,血清Klotho、IFN-γ、IL-2水平表达降低,联合血清FGF23/Klotho、Th1/Th2细胞因子预测医院感染、评估预后的价值较高。展开更多
文摘The klotho gene has been identified as an aging suppressor that encodes a protein involved in cardiovascular disease （CVD）. The inac- tivation of the klotho gene causes serious systemic disorders resembling human aging, such as atherosderosis, diffuse vascular calcification and shortened life span. Klotho has been demonstrated to ameliorate vascular endothelial dysfunction and delay vascular calcification. Fur- thermore, klotho gene polymorphisms in the human are associated with various cardiovascular events. Recent experiments show that klotho may reduce transient receptor potential canonical6 （TRPC6） channels, resulting in protecting the heart from hypertrophy and systolic dys- function. Fibroblast growth factor23 （FGF23） is a bone-derived hormone that plays an important role in the regulation of phosphate and vi- tamin D metabolism. FGF23 accelerates urinary phosphate excretion and suppresses 1,25-dihydroxy vitaminD3 （1,25（OH）2D3）synthesis in the presence ofFGF receptorl （FGFR1） and its co-receptor ldotho, principally in the kidney. The hormonal affects of circulating klotho pro- tein and FGF23 on vascular and heart have contributed to an understanding of their roles in the pathophysiology of arterial stiffness and left ventricular hypertrophy. Klotho and FGF23 appear to play a critical role in the pathogenesis of vascular disease, and may represent a novel potential therapeutic strategy for clinical intervention.
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.
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.
文摘目的观察血清成纤维生长因子-23(fibroblast growth factor 23,FGF23)/抗衰老基因Klotho、辅助性T淋巴细胞(helper T lymphocytes,Th)1/Th2细胞因子在老年终末期肾病患者中的表达,并分析对医院感染的预测和预后的影响。方法选取2021年1月1日至2022年12月31日自贡市精神卫生中心(自贡市老年病医院)收治的106例老年终末期肾病患者,男65例,年龄范围60~84岁,年龄(67.21±3.07)岁,女41例,年龄范围60~84岁,年龄(67.65±2.98)岁,于入院第2天检测血清FGF23、抗衰老基因Klotho、Th1细胞因子[γ干扰素(interferon-γ,IFN-γ)、白介素2(interleukin-2,IL-2)]、Th2细胞因子(IL-4、IL-10)水平,进行急性生理功能及慢性健康状况评分Ⅱ(acute physiology and chronic health status scoring systemⅡ,APACHEⅡ)评估。根据住院期间是否发生医院感染分为感染组(28例)、未感染组(78例),比较两组各项血清指标及APACHEⅡ评分水平,分析各项指标与APACHEⅡ评分的相关性。随访3个月统计患者生存预后[生存(71例)、死亡(35例)],比较不同预后患者血清FGF23、Klotho、IFN-γ、IL-2、IL-4、IL-10水平,分析各项指标对医院感染及预后的预测价值及临床效用。结果106例老年终末期肾病患者根据住院期间是否发生医院感染分为感染组(28例)、未感染组(78例),随访3个月后生存71例、死亡35例。入院第2天感染组血清FGF23、IL-4、IL-10水平及APACHEⅡ评分分别为(78.64±20.16)ng/mL、(20.14±1.48)μg/L、(22.47±2.56)μg/L、(26.38±6.51)分,未感染组分别为(60.17±16.83)ng/mL、(16.25±1.21)μg/L、(19.52±1.86)μg/L、(22.97±6.45)分,感染组血清FGF23、IL-4、IL-10水平及APACHEⅡ评分均高于未感染组(P<0.05);入院第2天感染组血清Klotho、IFN-γ、IL-2水平分别为(34.95±12.62)ng/mL、(22.19±1.69)μg/L、(28.73±2.95)μg/L,未感染组分别为(51.61±16.08)ng/mL、(25.31±1.74)μg/L、(33.95±1.52)μg/L,感染组血清Klotho、IFN-γ、IL-2水平均低于未感染组(P<0.05);血清FGF23、IL-4、IL-10水平与APACHEⅡ评分呈正相关(相关系数r=0.629、0.597、0.612,P均<0.05),血清Klotho、IFN-γ、IL-2水平与APACHEⅡ评分呈负相关(相关系数r=-0.632、-0.718、-0.701、0.597,P均<0.05);死亡患者入组后1个月血清FGF23、IL-10、IL-4水平分别为(77.49±21.85)ng/mL、(24.76±4.77)μg/L、(24.81±6.28)μg/L,生存患者分别为(58.92±16.94)ng/mL、(18.10±3.82)μg/L、(13.57±4.38)μg/L,死亡患者入组后1个月血清FGF23、IL-10、IL-4水平高于生存患者(P<0.05);死亡患者入组后1个月血清Klotho、IFN-γ、IL-2水平分别为(30.03±11.76)ng/mL、(20.33±2.63)μg/L、(27.19±4.91)μg/L,生存患者分别为(55.68±17.02)ng/mL、(26.54±4.79)μg/L、(35.22±5.64)μg/L,死亡患者入组后1个月血清Klotho、IFN-γ、IL-2水平低于生存患者(P<0.05);血清FGF23、Klotho、IFN-γ、IL-2、IL-4、IL-10预测终末期老年肾病患者发生医院感染、生存预后曲线下面积分别为0.904(OR:0.832~0.953)、0.911(OR:0.840~0.958),且具有良好临床效用(P<0.05)。结论老年终末期肾病患者血清FGF23/Klotho、Th1/Th2细胞因子水平失衡,合并感染患者血清FGF23、IL-10、IL-4水平异常升高,血清Klotho、IFN-γ、IL-2水平表达降低,联合血清FGF23/Klotho、Th1/Th2细胞因子预测医院感染、评估预后的价值较高。
