The hypoxia-inducible factor-1α activates ectopic production of fibroblast growth factor 23 in tumor-induced osteomalacia

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.

Significance of serum fibroblast growth factor-23 and miR-208b in pathogenesis of atrial fibrillation and their relationship with prognosis

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.

血清脂联素、成纤维生长因子-23在心脏瓣膜置换术患者预后中的评估价值

目的探讨血清脂联素、成纤维生长因子-23(FGF23)水平在心脏瓣膜置换术患者预后中的评估价值。方法选取行心脏瓣膜置换术的患者98例为研究组。根据研究组患者的预后情况分为预后良好组(n=67)和预后不良组(n=31)。选取同期健康体检者90例为对照组。采用Spearman法分析血清脂联素、FGF23水平分别与血浆N末端B型利钠肽前体(NT-proBNP)水平和急性生理学与慢性健康状况评分系统Ⅱ(APACHEⅡ)评分的相关性。采用多因素Logistic回归分析法分析心脏瓣膜置换术患者预后的影响因素。绘制受试者工作特征(ROC)曲线分析血清脂联素、FGF23水平对心脏瓣膜置换术患者预后的预测价值。结果研究组血清FGF23、NT-proBNP水平、APACHEⅡ评分高于对照组,血清脂联素水平低于对照组,差异有统计学意义(P<0.05)。预后不良组血清FGF23、NT-proBNP水平和APACHEⅡ评分高于预后良好组,血清脂联素水平低于预后良好组,差异有统计学意义(P<0.05)。患者的血清FGF23水平与NT-proBNP水平、APACHEⅡ评分呈正相关(P<0.05)。血清脂联素水平与NT-proBNP水平、APACHEⅡ评分呈负相关(P<0.05)。血清脂联素、FGF23、NT-proBNP水平和APACHEⅡ评分为心脏瓣膜置换术患者预后的影响因素(P<0.05)。血清脂联素、FGF23单独预测和联合预测心脏瓣膜置换术患者预后的曲线下面积(AUC)分别为0.862、0.807、0.911。脂联素、FGF23联合预测的AUC大于单独预测,差异有统计学意义(P<0.05)。结论血清脂联素、FGF23联合预测心脏瓣膜置换术患者预后的效果较好。血清脂联素、FGF23有望成为评估心脏瓣膜置换术患者预后效果的有效指标。

外周血Lp-PLA2和FGF23水平变化与脑梗死后认知功能障碍的相关性

目的分析外周血脂蛋白相关磷脂酶A2(Lp-PLA2)、成纤维细胞生长因子23(FGF23)水平变化与脑梗死后患者认知功能障碍的相关性。方法选取2019-04—2022-12邯郸市中心医院收治的160例脑梗死患者为研究对象,根据患者是否发生认知功能障碍分为认知障碍组和非认知障碍组,对比2组基线资料及外周血Lp-PLA2、FGF23水平,并采用Logistic回归分析患者发生认知功能障碍的影响因素,采用Pearson相关性分析外周血Lp-PLA2、FGF23与简易智力状态评价量表(MMSE)评分的关系,采用ROC曲线评估外周血Lp-PLA2、FGF23对脑梗死后患者认知功能障碍的预测价值。结果160例脑梗死患者中,48例(30.00%)发生认知功能障碍。认知障碍组患者的平均年龄、高血压、糖尿病、吸烟、文化程度、MMSE评分及血清Lp-PLA2、FGF23水平等方面与非认知障碍组相比,差异有统计学意义(P<0.05)。Logistic回归分析显示,年龄、高血压、糖尿病、吸烟、文化程度低及血清Lp-PLA2、FGF23水平升高是影响脑梗死后认知功能障碍发生的独立危险因素(P<0.05)。Pearson相关性分析显示,脑梗死患者血清Lp-PLA2、FGF23水平与MMSE评分呈负相关(P<0.05)。ROC曲线显示,Lp-PLA2的曲线下面积为0.770,FGF23的曲线下面积为0.779,联合检测的曲线下面积为0.873(P<0.05),表示两者联合检测可作为评价脑梗死后认知功能障碍的有效指标。结论Lp-PLA2、FGF23在脑梗死后认知功能障碍患者血清中均呈高表达,二者联合检测有助于提高对脑梗死后认知功能障碍的预测价值。

血清维生素D结合蛋白、FGF23、Klotho与乳腺癌骨转移的相关性分析

目的骨转移是乳腺癌常见的并发症之一,严重影响患者的生存和预后。本研究旨在探究血清维生素D结合蛋白(vitamin D⁃binding protein,VDBP)、成纤维细胞生长因子23(fibroblast growth factor 23,FGF23)和Klotho蛋白在乳腺癌骨转移中的表达及临床意义。方法收集95例来自本院2019⁃08⁃01至2021⁃08⁃01的女性乳腺癌患者作为研究对象,经影像学和组织病理学方式诊断是否发生骨转移,将患者分为骨转移组36例,非骨转移组59例。分析两组患者的临床病理特征;采集患者外周血样本,通过ELISA对血清中VDBP、FGF23和Klotho进行定量分析;使用Spearman相关分析进行指标间的关联性分析;Logistic回归分析乳腺癌发生骨转移的影响因素;ROC曲线分析血清VDBP、FGF23和Klotho水平预测乳腺癌发生骨转移的价值。结果骨转移和非骨转移乳腺癌病理分级比较有统计学意义(P<0.05)。骨转移和非骨转移乳腺癌患者血清中VDBP、FGF23及Klotho的水平依次为:(80.35±29.34)和(115.18±48.69)ng/mL、(658.35±201.19)和(405.36±154.42)pg/mL以及(155.82±40.29)和(229.35±72.46)pg/mL,两组比较差异有统计学意义(P<0.05)。Spearman相关性分析显示,骨转移乳腺癌患者血清中VDBP水平与乳腺癌病理分级相关(P<0.05);FGF23和Klotho水平与病理分级、是否骨痛以及转移部位有关(P<0.05)。VDBP、FGF23和Klotho水平均为乳腺癌骨转移发生的独立影响因素(P<0.05)。ROC曲线结果显示,VDBP、FGF23及Klotho预测乳腺癌患者发生骨转移的曲线下面积依次为:0.733、0.806、0.761,最佳截断值为:81.56 ng/mL、573.501 pg/mL和201.193 pg/mL;3个指标联合诊断的曲线下面积为0.820,高于单一指标诊断的曲线下面积。结论血清VDBP、FGF23及Klotho水平可作为乳腺癌骨转移的参考指标,在乳腺癌骨转移的临床诊断上具有一定应用前景。

17β-estradiol inhibits TGF-β-induced collagen gel contraction mediated by human Tenon fibroblasts via Smads and MAPK signaling pathways

AIM:To investigate the impact of 17β-estradiol on the collagen gels contraction(CGC)and inflammation induced by transforming growth factor(TGF)-βin human Tenon fibroblasts(HTFs).METHODS:HTFs were three-dimensionally cultivated in type I collagen-generated gels with or without TGF-β(5 ng/mL),17β-estradiol(12.5 to 100μmol/L),or progesterone(12.5 to 100μmol/L).Then,the collagen gel diameter was determined to assess the contraction,and the development of stress fibers was analyzed using immunofluorescence staining.Immunoblot and gelatin zymography assays were used to analyze matrix metalloproteinases(MMPs)and tissue inhibitors of metalloproteinases(TIMPs)being released into culture supernatants.Enzyme-linked immunosorbent assay(ELISA)and reverse transcription-quantitative polymerase chain reaction(RT-PCR)were used to detect interleukin(IL)-6,monocyte chemoattractant proteins(MCP)-1,and vascular endothelial growth factor(VEGF)in HTFs at the translational and transcriptional levels.The phosphorylation levels of Sma-and Mad-related proteins(Smads),mitogen-activated protein kinases(MAPKs),and protein kinase B(AKT)were measured by immunoblotting.Statistical analysis was performed using either the Tukey-Kramer test or Student’s unpaired t-test to compare the various treatments.RESULTS:The CGC caused by TGF-βin HTFs was significantly inhibited by 17β-estradiol(25 to 100μmol/L),and a statistically significant difference was observed when comparing the normal control group with 17β-estradiol concentrations exceeding 25μmol/L(P<0.05).The suppressive impact of 17β-estradiol became evident 24h after administration and peaked at 72h(P<0.05),whereas progesterone had no impact.Moreover,17β-estradiol attenuated the formation of stress fibers,and the production of MMP-3 and MMP-1 in HTFs stimulated by TGF-β.The expression of MCP-1,IL-6,and VEGF mRNA and protein in HTFs were suppressed by 100μmol/L 17β-estradiol(P<0.01).Additionally,the phosphorylation of Smad2 Smad3,p38,and extracellular signal-regulated kinase(ERK)were downregulated(P<0.01).CONCLUSION:17β-estradiol significantly inhibits the CGC and inflammation caused by TGF-βin HTFs.This inhibition is likely related to the suppression of stress fibers,inhibition of MMPs,and attenuation of Smads and MAPK(ERK and p38)signaling.17β-estradiol may have potential clinical benefits in preventing scar development and inflammation in the conjunctiva.

小于胎龄儿生后血清Klotho和成纤维细胞生长因子23水平变化及其与生长发育的关系

目的:探讨小于胎龄儿(SGA)生后血清Klotho和成纤维细胞生长因子23(FGF23)水平变化,并阐明其与生长发育的关系。方法:选取35例SGA和53例适于胎龄儿(AGA)作为研究对象,分为SGA组(n=35)和AGA组(n=53),其中早产儿组51例,早产SGA组20例,早产AGA组31例;足月儿组37例,足月SGA组15例,足月AGA组22例。收集各组新生儿的临床资料,分别检测新生儿生后第7和14天血清Klotho和FGF23水平及临床生化指标,分析新生儿生后第7和14天血清Klotho及FGF23水平与新生儿体质量、身长、头围、胸围和考普氏(Kapu)指数等各项生长发育指标及钙磷代谢的相关性。结果:与AGA组比较,SGA组新生儿出生体质量、身长、头围、胸围和Kapu指数均明显降低(P<0.05)。生后第7和14天,与早产儿组比较,足月儿组新生儿血清Klotho和FGF23水平均明显升高(P<0.01);与生后第7天比较,生后第14天早产儿组和足月儿组新生儿血清Klotho水平均明显升高(P<0.01),FGF23水平均明显降低(P<0.01)。与AGA组比较,SGA组新生儿生后第7和14天血清Klotho和FGF23水平明显降低(P<0.05或P<0.01);与生后第7天比较,生后第14天AGA组和SGA组新生儿血清Klotho水平明显升高(P<0.01),FGF23水平明显降低(P<0.05或P<0.01)。与早产AGA组比较,早产SGA组新生儿生后第7和14天血清Klotho和FGF23水平均明显降低(P<0.05或P<0.01)。与足月AGA组比较,足月SGA组新生儿生后第7和14天血清Klotho和FGF23水平均明显降低(P<0.05或P<0.01)。SGA组新生儿生后第7天血清Klotho和FGF23水平与胎龄、体质量、身长、头围、胸围和Kapu指数等生长发育指标均呈正相关关系(P<0.05或P<0.01),血清Klotho水平与FGF23水平呈正相关关系(P<0.05)。钙磷代谢方面,SGA组新生儿生后第7天血清Klotho水平与血清磷水平呈正相关关系(P<0.01);FGF23水平与血清钙和磷水平均呈正相关关系(P<0.05或P<0.01)。结论:Klotho和FGF23蛋白与新生儿生长发育及磷酸盐代谢有密切关联。SGA新生儿生后血清Klotho和FGF23水平较低,但随着各器官发育逐渐完善,Klotho分泌增加,而FGF23水平降低可能是机体的代偿性反应。

Significant roles of anti-aging protein klotho and fibroblast growth factor23 in cardiovascular disease

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.

Distribution and localization of fibroblast growth factor-8 in rat brain and nerve cells during neural stem/progenitor cell differentiation

The present study explored the distribution and localization of fibroblast growth factor-8 and its potential receptor, fibroblast growth factor receptor-3, in adult rat brain in vivo and in nerve cells during differentiation of neural stem/progenitor cells in vitro. Immunohistochemistry was used to examine the distribution of fibroblast growth factor-8 in adult rat brain in vivo. Localization of fibroblast growth factor-8 and fibroblast growth factor receptor-3 in cells during neural stem/progenitor cell differentiation in vitro was detected by immunofluorescence. Flow cytometry and immunofluorescence were used to evaluate the effect of an anti-fibroblast growth factor-8 antibody on neural stem/progenitor cell differentiation and expansion in vitro. Results from this study confirmed that fibroblast growth factor-8 was mainly distributed in adult midbrain, namely the substantia nigra, compact part, dorsal tier, substantia nigra and reticular part, but was not detected in the forebrain comprising the caudate putamen and striatum. Unusual results were obtained in retrosplenial locations of adult rat brain. We found that fibroblast growth factor-8 and fibroblast growth factor receptor-3 were distributed on the cell membrane and in the cytoplasm of nerve cells using immunohistochemistry and immunofluorescence analyses. We considered that the distribution of fibroblast growth factor-8 and fibroblast growth factor receptor-3 in neural cells corresponded to the characteristics of fibroblast growth factor-8, a secretory factor. Addition of an anti-fibroblast growth factor-8 antibody to cultures significantly affected the rate of expansion and differentiation of neural stem/progenitor cells. In contrast, addition of recombinant fibroblast growth factor-8 to differentiation medium promoted neural stem/progenitor cell differentiation and increased the final yields of dopaminergic neurons and total neurons. Our study may help delineate the important roles of fibroblast growth factor-8 in brain activities and neural stem/progenitor cell differentiation.

Fibroblast growth factor 23 and bone mineralisation

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.

血清成纤维细胞生长因子23、S100A12对老年糖尿病患者动脉粥样硬化性心血管病的预测价值

目的探讨血清成纤维细胞生长因子23(FGF23)、S100A12对老年糖尿病患者动脉粥样硬化性心血管病(ASCVD)的预测价值。方法选取133例老年糖尿病患者为研究对象,根据是否合并ASCVD,将其分为糖尿病组(n=59)和ASCVD组(n=74)。选取同期行体检的健康者为对照组(n=56)。检测并比较血清FGF23、S100A12表达水平。采用多因素Logistic回归分析法分析老年糖尿病患者发生ASCVD的影响因素。评估血清FGF23、S100A12水平对ASCVD发生的预测价值。结果ASCVD组高血压比例、空腹血糖、糖尿病病程高于或长于糖尿病组,差异有统计学意义(P<0.05)。ASCVD组血清FGF23、S100A12表达水平高于糖尿病组、对照组,差异有统计学意义(P<0.05)。高血压、血清FGF23、S100A12表达水平是影响老年糖尿病患者发生ASCVD的独立影响因素(P<0.05)。血清FGF23、S100A12单独预测老年糖尿病患者发生ASCVD的曲线下面积(AUC)分别为0.755、0.874,二者联合预测的AUC为0.934,灵敏度和特异度分别为82.43%、89.83%。血清FGF23、S100A12联合预测优于其单独预测(P<0.05)。结论老年糖尿病患者的血清FGF23、S100A12水平均升高。血清FGF23、S100A12联合预测老年糖尿病患者发生ASCVD的价值相较单独预测更高。

连接蛋白2和FGF23在房颤介导心肌病兔心房组织中的表达

目的 探究连接蛋白2(JP2)和成纤维细胞生长因子23(FGF23)在房颤介导心肌病(AMC)兔中的表达规律。方法 通过左心房快速起搏法建立心房颤动(AF)模型,4周后行超声心动图检查,射血分数下降>10%纳入AMC组,否则为AF组,对照组只植入起搏器不起搏。最终成功建立AF动物模型11只,其中AF组6只,AMC组5只,对照组6只。超声心动图检测左室舒张末期内径(LVEDD)、左室收缩末期内径(LVESD)、左室射血分数(LVEF)等指标,酶联免疫吸附法(ELISA)检测血清JP2和FGF23水平。处死动物后,取心房组织,Western blot和RT-qPCR检测JP2和FGF23蛋白及mRNA表达。结果 与对照组相比,AMC组左房内径、右房内径、右室内径增大,LVEF降低,与AF组相比,AMC组LVEF降低,主动脉增宽,右室扩大。与对照组相比,AF组左房心肌细胞FGF23(P<0.001)、JP2(P<0.01)的表达均明显增加,而AMC组JP2表达降低(P<0.001)。与AF组相比,AMC组FGF23和JP2的表达下降。与对照组相比,AF组FGF23和JP2血浆浓度升高,AMC组FGF23水平升高。与AF组相比,AMC组FGF23和JP2血浆浓度偏低。结论 在AMC兔模型中,FGF23表达增加,JP2表达下降。

新生血管形成过程中miR-296-5p对FGF23的调控作用

目的研究miR-296-5p通过调节成纤维细胞生长因子23(FGF23)在新生血管生成过程中发挥的调控作用。方法用血管内皮生长因子(VEGF)诱导人脐静脉内皮细胞(HUVECs),构建模拟新生血管形成的体外模型,通过RT-qPCR比较对照组与新生血管组中miR-296-5p的表达水平。通过细胞转染构建miR-296-5p高表达组、miR-296-5p低表达组以及对照组细胞,比较3组细胞的迁移和成管能力,并通过蛋白免疫印迹实验比较3组FGF23的表达水平。结果与未经处理的对照组相比,VEGF诱导的新生血管组中miR-296-5p的表达水平显著增加(P<0.001)。与对照组比较,miR-296-5p低表达组的迁移距离和成管数均降低(P<0.001和P<0.05);而miR-296-5p高表达组的迁移距离和成管数均增加(P<0.001和P<0.01)。与对照组比较,miR-296-5p低表达组的FGF23表达水平明显降低(P<0.01);而miR-296-5p高表达组FGF23表达水平明显升高(P<0.01)。结论miR-296-5p可通过上调FGF23的表达促进新生血管生成。

Local inhibition of matrix metalloproteinases reduced M2 macrophage activity and impeded recovery in spinal cord transected rats after treatment with fibroblast growth factor-1 and nerve grafts

Alternatively activated macrophages （M2 macrophages） promote central nervous system regeneration. Our previous study demonstrated that treatment with peripheral nerve grafts and fibroblast growth factor-1 recruited more M2 macrophages and improved partial functional recovery in spinal cord transected rats. The migration of macrophages is matrix metalloproteinase （MMP） dependent. We used a general inhibitor of MMPs to influence macrophage migration, and we examined the migration of macrophage populations and changes in spinal function. Rat spinal cords were completely transected at Ts, and 5 mm of spinal cord was removed （group T）. In group R, spinal cord-transected rats received treatment with fibroblast grow th factor- 1 and peripheral nerve grafts. In group RG, rats received the same treatment as group R with the addition of 200 μM GM6001 （an MMP inhibitor） to the fibrin mix. We found that MMP-9, but not MMP- 2, was upregulated in the graft area of rats in group R. Local application of the MMP inhibitor resulted in a reduction in the ratio of arginase-1 （M2 macrophage subset）/inducible nitric oxide synthase-postive cells. When the MMP inhibitor was applied at 8 weeks postoperation, the partial functional recovery observed in group R was lost. This effect was accompanied by a decrease in brain-derived neurotrophic factor levels in the nerve graft. These results suggested that the arginase-1 positive population in spinal cord transected rats is a migratory cell population rather than the phenotypic conversion of early iNOS^＋ cells and that the migration of the arginase-1^＋ population could be regulated locally. Simultaneous application of MMP in- hibitors or promotion of MMP activity for spinal cord injury needs to be considered if the coadministered treatment involves M2 recruitment.

Tumor-induced osteomalacia with elevated fibroblast growth factor 23: a case of phosphaturic mesenchymal tumor mixed with connective tissue variants and review of the literature

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.

FGF23对慢性肾脏病的矿物质和骨代谢异常的作用及中药干预的研究

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。

雷火灸、穴位贴敷治疗慢性肾脏病3~4期的疗效及对血清TGF-β1、Klotho、FGF23水平的影响

目的:研究雷火灸、穴位贴敷治疗慢性肾脏病3~4期的疗效及对血清转化生长因子-β1(TGF-β1)、Klotho蛋白(Klotho)、成纤维生长因子23(FGF23)水平的影响。方法:2022年1月~2023年1月我院收治的慢性肾脏病3~4期患者92例,分为对照组与试验组,各46例,方法为随机数字表法。对照组予以常规西医治疗,试验组在对照组的基础上予以雷火灸、穴位贴敷治疗,两组均治疗2周。比较两组治疗2周后疗效,治疗前、治疗2周后血清TGF-β1、Klotho、FGF23水平、肾功能、免疫功能,治疗期间不良反应发生情况。结果:与对照组治疗2周后的总有效率(71.74%)比较,试验组总有效率更高(91.30%,P<0.05)。较治疗前,治疗2周后两组血清TGF-β1、FGF23、尿素氮(BUN)、血肌酐(Scr)水平,全血辅助性T细胞17(Th17)水平,24h尿蛋白定量降低,且试验组更低(P<0.05)。较治疗前,治疗2周后两组全血调节性T细胞(Treg)水平,血清免疫球蛋白G(IgG)、免疫球蛋白A(IgA)、免疫球蛋白M(IgM)、Klotho水平升高,且试验组更高(P<0.05)。治疗期间,两组不良反应发生率接近,均未影响继续治疗(P>0.05)。结论:雷火灸、穴位贴敷治疗慢性肾脏病3~4期的疗效较好,可改善肾功能、免疫功能,调节血清TGF-β1、Klotho、FGF23水平表达,降低肾脏损伤,安全性良好。

终末期肾脏病患者血清FGF23与心衰及死亡发生风险的前瞻性队列研究

目的探讨终末期肾脏病(ESRD)患者成纤维细胞生长因子-23(FGF23)血清浓度与心力衰竭及全因死亡的相关性。方法采用前瞻性队列研究,纳入医院肾脏内科收治的无心衰症状的ESRD患者,采用基线问卷和体格检查、超声心动图检查、实验室检查收集患者数据,采用酶联免疫吸附法(ELISA)检测患者血清FGF23浓度。随访时间2年,以随访发生新发的心力衰竭(ACC/AHA stage C-D)和全因死亡为复合终点结局事件,采用Cox比例风险模型分析患者发生结局事件的危险因素,通过亚组分析和交互作用分析,进一步探讨FGF23与结局事件的关联在不同亚组中是否存在异质性。结果该研究最终纳入ESRD患者107例,平均年龄(52.00±12.51)岁,男性39(36.45%)例,中位随访时间为23个月(21,25个月),出现结局事件32(29.9%)例,其中新发心衰22(20.6%)例,全因死亡10(9.3%)例。该研究结果显示结局事件组患者血清FGF23浓度显著高于非事件组[(4.40±1.16)pmol/ml vs(3.85±0.82)pmol/ml,P<0.05]。Cox比例风险模型结果显示升高的FGF23可以增加ESRD患者发生结局事件的风险(HR=1.730,95%CI:1.164~2.570,P=0.007)。亚组分析显示FGF23水平与性别对于结局事件发生风险存在交互作用,尤其在男性ESRD患者中升高的FGF23风险更高(P_(-交互作用)<0.05)。结论升高的血清FGF23是ESRD患者发生心衰和全因死亡的独立危险因素,尤其在男性患者中风险更高。

血清CERP、SF、α-Klotho、FGF-23水平在2型糖尿病患者白蛋白尿进展中的预测价值

目的分析血清铜蓝蛋白(ceruloplasmin,CERP)、血清铁蛋白(serum ferritin,SF)、α-Klotho、成纤维细胞生长因子-23(fibroblast growth factor,FGF-23)在2型糖尿病患者白蛋白尿进展中的预测价值。方法选择2020年6月至2022年5月沭阳医院内分泌科因控制血糖重复收住院的120例2型糖尿病患者进行回顾性队列研究,将首次住院和第二次住院的资料分别作为基线资料和随访资料。根据基线中患者白蛋白尿情况将其分为3组:无白蛋白尿组、微量白蛋白尿组、大量白蛋白尿组,比较3组患者中CERP、SF、α-Klotho、FGF-23水平的差异;根据随访资料评价白蛋白尿进展的情况,比较白蛋白尿进展的患者与未进展的患者的基线临床资料及其CERP、SF、α-Klotho、FGF-23水平的差异,采用logistic回归分析白蛋白尿进展的影响因素,采用ROC曲线分析白蛋白尿进展的预测指标。结果随着2型糖尿病患者尿白蛋白水平升高,血清CERP、SF、FGF-23水平升高,而α-Klotho水平降低(P<0.05);白蛋白尿进展的2型糖尿病患者的糖尿病病程长于未进展的2型糖尿病患者,其二甲双胍及SGLT2抑制剂(SGLT2i)使用比例、α-Klotho水平均低于未进展的2型糖尿病患者,其高血压比例、FBG、UA、CERP、SF、FGF-23水平均高于未进展的2型糖尿病患者,差异有统计学意义(P<0.05);logistic回归分析显示CERP、SF、FGF-23水平升高是白蛋白尿进展的危险因素,而使用二甲双胍及SGLT2i以及α-Klotho水平的升高均是白蛋白尿进展的保护因素;ROC曲线分析显示首次住院时血清CERP、SF、α-Klotho、FGF-23的水平对白蛋白尿进展具有预测价值,logistic回归方程的联合指标预测尿白蛋白的灵敏度和特异性均优于单一指标。结论血清CERP、SF、FGF-23水平的升高及α-Klotho水平的降低与2型糖尿病患者中白蛋白尿进展有关,检测4项血清指标对白蛋白尿进展具有预测价值。

FGF23对支气管上皮细胞生长、免疫平衡和上皮间充质转化的影响

目的探究成纤维细胞生长因子23(FGF23)对支气管上皮细胞16HBE生长、免疫平衡和上皮间充质转化(EMT)的影响。方法使用Lipofectamine 3000转染试剂对16HBE细胞分别转染NC-shRNA或FGF23-shRNA。转染后,使用10 ng/mL TGF-β1处理细胞48 h。16HBE细胞分为对照组、NC-shRNA组、FGF23-shRNA组、TGF-β1组、NC-shRNA+TGF-β1组和FGF23-shRNA+TGF-β1组。通过CCK-8法检测细胞增殖。使用ELISA试剂盒检测16HBE细胞上清液中IFN-γ、IL-4、IL-17和IL-10的水平。通过qRT-PCR、Western blot或免疫荧光染色检测16HBE细胞中FGF23、Klotho、FGFR4、E-cadherin、α-SMA和N-cadherin的mRNA或蛋白表达水平。结果与TGF-β1组相比,FGF23-shRNA+TGF-β1组的OD 450nm值降低(P<0.05)。与TGF-β1组相比,FGF23-shRNA+TGF-β1组的IFN-γ和IL-10的水平升高,而IL-4和IL-17降低(P<0.05)。与TGF-β1组相比,FGF23-shRNA+TGF-β1组的E-cadherin蛋白表达水平升高,而α-SMA降低(P<0.05)。与TGF-β1组相比,FGF23-shRNA+TGF-β1组的E-cadherin相对荧光强度升高,而N-cadherin降低(P<0.05)。与TGF-β1组相比,FGF23-shRNA+TGF-β1组的FGF23和FGFR4的mRNA和蛋白表达水平均降低,而Klotho均升高(P<0.05)。结论下调FGF23抑制了TGF-β1诱导的16HBE细胞的生长和EMT过程,并纠正了Th1/Th2和Treg/Th17的失衡,FGF23-Klotho-FGFR4信号可能是哮喘治疗的一种分子靶标。