Fibroblast growth factor 2 modulates extracellular purine metabolism by upregulating ecto-5′-nucleotidase and adenosine deaminase in cultured rat spinal cord astrocytes

Purinergic signaling via ATP and adenosine produced by astrocytes is one pathway underlying neuron–glia interactions in the central nervous system (CNS). In production of purines, extracellular metabolism of released purines via ecto-enzymes is important. The expression and activities of these enzymes are altered under pathological conditions. Production of fibroblast growth factor 2 (FGF2) is increased under pathological conditions, and this has various effects on astrocytes. Here, we investigated the effects of FGF2 on purine metabolism in cultured rat spinal cord astrocytes. Astrocytes rapidly metabolized purines added to the extracellular solution. FGF2 increased extracellular metabolism of AMP to adenosine and of adenosine to inosine by upregulating ecto-5′-nucleotidase and adenosine deaminase (ADA), respectively. ADA activity and protein were detected both in the cytosol and external solution of astrocytes, and their levels were markedly increased by FGF2. FGF2 also increased metabolism of endogenously released ATP, resulting in a transient increase in adenosine and substantial accumulation of extracellular inosine. Moreover, FGF2 increased ATP release by upregulating the activity of gap junction hemichannels. These data show that FGF2 regulates purine production in astrocytes and suggest that extracellular ADA released by astrocytes plays an important role in extracellular purine metabolism in the CNS.     

Impact of hepatitis virus infection on arterial calcification among incident hemodialysis patients

BackgroundThe impact of hepatitis virus infection on arterial calcification (AC) was not studied.ObjectiveTo study the prevalence, severity and distribution of AC in incident hemodialysis patients with hepatitis B and C viral infection.Cases and methods172 stage 5 CKD adults (98 male and 74 female) were included; 58 of them were seronegative for both hepatitis B and C (SN group), 48 were positive for hepatitis B virus infection (HBV group) and 66 were hepatitis C virus positive (HCV group). Beside histopathology of the obtained arterial samples, all these cases were examined for body mass index (BMI), serum calcium (Ca), phosphorus (P), alkaline phosphatase (AP), serum albumin, uric acid (UA), alanine transaminase (ALT), parathormone (PTH), fibroblast growth factor 23(FGF23), interleukin 6 (IL6), and 25 hydroxy vitamin D (25 (OH) vit D), hemoglobin concentration, and serum ferritin.Results86 (50%) of the cases had AC; 11 of them were in SN group (19%), 9 in HBV group (18.8%) and all the 66 HCV group (100%). In SN group, 4 had intimal calcification, 5 had medial calcification, and 2 had both intimal and medial calcification. In HBV group, 9 had intimal calcification, while no cases were encountered with either medial or both site calcifications. In HCV group, 16 had intimal calcification, 31 had medial calcification, and 19 had both intimal and medial calcification. Calcification was in the form of spots in one case in SN group, and 6 cases in HBV group, a single plaque of calcification in 5 cases of SN group, 3 cases of HBV group, and 16 cases of HCV group, multiple plaques were detected in 4 cases in SN group, and 31 cases in HCV group, and diffuse calcification in one case in SN group, and 19 cases in HCV group.In HBV group, calcification was only detected in patients with high viremia, while all patients with low or moderate viremia were devoid of calcification. In HCV group, all patients with low viremia had intimal solitary plaque of calcification, all patients with moderate viremia had multiple plaques of medial calcification, while all patients with high viremia had diffuse intimal and medial calcification. Both groups of viral hepatitis were significantly different in comparison to SN group in either distribution or calcification score (P < 0.001 in all).HBV group had significantly lower serum P, CaxP and PTH in comparison to SN group (4.6 ± 0.66 vs. 5.45 ± 0.77 mg/dL, 36.4 ± 7.2 vs. 44.1 ± 8.69, and 348 ± 65.4 vs. 405.9 ± 83.2 pg/mL, P < 0.001, <0.001, and 0.035 respectively). On the other hand, HCV group did not show any significant difference in any of the studied parameters compared to SN group.ConclusionHCV positive patients are more prone to develop AC that is more extensive. HBV positive patients were less likely to have arterial medial calcification, probably related to lower serum phosphorus, CaxP product and PTH. HCV infection should be added as risk factor for AC among CKD patients. Further studies are needed to confirm these findings.     

Fish and omega-3 fatty acid intake in relation to circulating fibroblast growth factor 23 levels in renal transplant recipients

Background and aimsA high circulating fibroblast growth factor 23 (FGF23) level is an independent risk factor for cardiovascular mortality in renal transplant recipients and the general population. N-3 fatty acids eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) may contribute to cardiovascular risk reduction. We investigated whether fish and EPA-DHA intake are related to FGF23 levels in renal transplant recipients.Methods and resultsWe performed a cross-sectional analysis in 619 stable renal transplant recipients (mean age 53 years, 57% male, estimated glomerular filtration rate [eGFR] 53 ± 20 mL/min/1.73 m²). Dietary intake was assessed by a 177-item food frequency questionnaire. Serum intact FGF23 was measured by ELISA. We examined differences in FGF23 levels across categories of fish and EPA-DHA intake using analysis of variance models adjusted for age, sex, dietary and lifestyle factors and key determinants of FGF23. Patients consumed on average 15 g of fish and 139 mg EPA-DHA/day. Median FGF23 was 62 pg/mL (IQR 43–98 pg/mL). Higher dietary EPA-DHA and fish intake were associated with lower serum FGF23 levels. Subgroup analyses revealed that particularly in patients with reduced renal function (eGFR <60 mL/min/1.73 m²), adjusted FGF23 levels (114, 79, 75 pg/mL, P = 0.0001) were inversely associated with tertiles of EPA-DHA intake. Similarly, we observed an inverse association between fish consumption and serum FGF23 levels in adjusted analyses.ConclusionA higher intake of fish and dietary n-3 fatty acids (EPA-DHA) is related to lower circulating FGF23 levels in renal transplant recipients. Further research is needed to assess the causality of this association and the clinical implications.     

Elevated Fibroblast Growth Factor 23 Exerts Its Effects on Placenta and Regulates Vitamin D Metabolism in Pregnancy of Hyp Mice

Fibroblast growth factor 23 (FGF23) functions in an endocrine fashion and requires α‐Klotho to exert its effects on the target organs. We have recently demonstrated that the human placenta also expresses α‐Klotho, which led us to hypothesize that FGF23 may exert effects on the placenta. Immunohistochemical analysis demonstrated the expression of FGF receptor 1 (FGFR1) as well as that of α‐Klotho in the feto‐maternal interface of both mouse and human normal‐term placentas, which suggested that these areas might be receptive to FGF23. Therefore, we next investigated whether FGF23 has some roles in the placenta using Hyp mice with high levels of circulating FGF23. Hyp and wild‐type (WT) females were mated with WT males, and the mothers and their male fetuses were analyzed. FGF23 levels in Hyp mothers were elevated. FGF23 levels were about 20‐fold higher in Hyp fetuses than in Hyp mothers, whereas WT fetuses from Hyp mothers exhibited low levels of FGF23, as did fetuses from WT mothers. We analyzed the placental gene expression and found that the expression of Cyp24a1 encoding 25OHD‐24‐hydroxylase, a target gene for FGF23 in the kidney, was increased in the placentas of fetuses from Hyp mothers compared with fetuses from WT mothers. In an organ culture of WT placentas, treatment with plasma from Hyp mothers markedly increased the expression of Cyp24a1, which was abolished by the simultaneous addition of anti‐FGF23 neutralizing antibody. The direct injection of recombinant FGF23 into WT placentas induced the expression of Cyp24a1. The increase in the placental expression of Cyp24a1 in fetuses from Hyp mothers resulted in decreased plasma 25‐hydroxyvitamin D levels. These results suggest that increased levels of circulating FGF23 in pathological conditions such as Hyp mice exerts direct effects on the placenta and affects fetal vitamin D metabolism via the regulation of Cyp24a1 expression. © 2014 American Society for Bone and Mineral Research.     

成纤维细胞生长因子21与代谢综合征的相关性研究

目的本研究通过对352名参与者进行5年的随访,探讨成纤维细胞生长因子（FGF-21）与代谢综合征（MS）发生发展的关系。方法记录参与者一般临床资料,采用酶联免疫吸附法（ELISA）测定基线及随访5年后参与者血清FGF-21浓度水平,对比分析MS组与非MS组间FGF21浓度水平的差异,并采用多因素Logistic回归分析FGF21是否为MS的独立危险因素。结果 MS组参与者基线FGF21浓度水平明显高于非MS组,差异有统计学意义（P〈0.05）;MS组参与者随访5年后FGF21浓度水平明显高于基线FGF21浓度水平,差异有统计学意义（P〈0.05）,非MS组参与者随访5年后血清FGF21浓度水平与基线FGF21浓度水平差异无统计学意义（P〉0.05）;多因素Logistic回归分析发现,腰围、BMI、TG、HOMA-IR、FGF21是影响MS发生的独立危险因素。结论血清FGF-21浓度水平高是MS发生的独立危险因素,未来有可能成为干预MS有效的分子靶点。     

Overexpression of Dmp1 fails to rescue the bone and dentin defects in Fam20C knockout mice

FAM20C is a kinase phosphorylating the small-integrin-binding ligand, N-linked glycoproteins (SIBLINGs), a group of extracellular matrix proteins that are essential for bone and dentin formation. Previously, we showed that Sox2-Cre;Fam20C^fl/fl mice had bone and dentin defects, along with hypophosphatemia and significant downregulation of dentin matrix protein 1 (DMP1). While the assumed phosphorylation failure of the SIBLINGs is likely associated with the defects in the Fam20C-deficient mice, it remains unclear if the downregulation of Dmp1 contributes to these phenotypes. In this study, we crossed 3.6?kb Col1-Dmp1 transgenic mice with 3.6?kb Col1-Cre;Fam20C^fl/fl mice to overexpress Dmp1 in the mineralized tissues of Fam20C conditional knockout (cKO) mice. X-ray, micro-computed tomography, serum biochemistry and histology analyses showed that expressing the Dmp1 transgene failed to rescue the bone and dentin defects, as well as the serum levels of FGF23 and phosphate in the Fam20C-cKO mice. These results indicated that the downregulation of Dmp1 may not directly associate with, or significantly contribute to the bone and dentin defects in the Fam20C-cKO mice.