Fibroblast Growth Factor 23 Levels Research Articles

Factors associated with impaired physical functionality in x-linked hypophosphatemia

Abstract X-linked hypophosphatemia (XLH) is a rare inherited disorder characterized by elevated levels of fibroblast growth factor-23 (FGF23), chronic hypophosphatemia, impaired bone mineralization and chronic long-term manifestations. Treatment for XLH has been mainly focused on normalizing its biochemical abnormalities. Despite treatment, patients with XLH often present impaired physical function and decreased quality of life (QoL). We hypothesize that physical functionality and QoL is more strongly associated with chronic pain and decreased muscle mass than persistent biochemical abnormalities or exposure to conventional treatment. We conducted an observational, cross-sectional study with patients with XLH. Clinical records and biochemical parameters were assessed. QoL surveys SF36v.2 and WOMAC were applied. Functional status was measured by a physiatrist and an occupational therapist. Appendicular lean mass (ALM) was measured and compared to age and sex-matched healthy controls. Enthesopathies and osteoarthritis were evaluated. Pain was assessed using the Brief Pain Inventory, the Visual Analog Scale and the Doleur Neuropathique-4 scales. Muscle strength was evaluated by the Quadriceps Muscle isometric Strength (QMS) and physical performance with the 6-minute walk test (6MWT) and the Functional Independence Measure (FIM) scale. A total of 30 patients were included: 21 females; median age of 32 years. All participants had significant functional deficits, chronic pain and reduced QoL. Limitations in daily activities were significantly associated with higher severity of pain, decreased ALM, lower QMS, and less distance in 6MWT (P<.05). Neither FIM scale, phosphate levels, FGF23, nor the lifetime exposure to conventional treatment were associated with these functional variables. In conclusion, impaired physical functionality in patients with XLH was associated with lower muscle mass, lower muscle strength and severe chronic pain. These findings highlight the importance of, in addition to optimizing the biochemical control of the disease, expanding patient care including pain prevention and management as well as comprehensive physical therapy and rehabilitation.

Pemafibrate ameliorates renal injury through induction of FGF21 and ketone body production in male mice.

Chronic kidney disease is a life-threatening disease worldwide. PPARα is a crucial transcriptional regulator of lipid metabolism and inflammation. Here, we examine whether a novel selective PPARα modulator, pemafibrate modulates renal injury in a model of unilateral ureteral obstruction (UUO). Administration of pemafibrate to wild-type (WT) mice led to reduction of renal dysfunction and fibrosis after UUO with accompanying increases in plasma levels of fibroblast growth factor (FGF) 21 and ketone body β-hydroxybutyrate (BHB). Treatment of WT mice with FGF21 or BHB precursor resulted in attenuation of renal fibrotic and inflammatory responses after UUO. Treatment of proximal tubular cells with FGF21 or BHB reduced expression of epithelial-mesenchymal transition markers. These findings suggest that pemafibrate could ameliorate renal damage, at least in part, by its abilities to increase the production of FGF21 and BHB.

Serum cytokine profile in women with type 1 diabetes mellitus in the III trimester of pregnancy and in their newborns

Background: Chronic hyperglycemia and abnormal glucose variability are established risk factors for perinatal complications. Abnormal fetal growth and diabetic fetopathy can be associated not only with carbohydrate metabolism disorders, but also with impaired production of cytokines, chemokines, and growth factors that regulate intercellular interactions. Aim: The aim of this study was to evaluate cytokine and growth factor levels in the blood serum of pregnant women with type 1 diabetes mellitus and in umbilical cord blood of their neonates, as well as assessing the associations of these levels with the development of fetal macrosomia and diabetic fetopathy. Materials and methods: This prospective study included 88 women with a singleton pregnancy and cesarean delivery. All the patients provided informed consent for participation. The study groups comprised individuals with type 1 diabetes mellitus (n = 32) and non-impaired glucose tolerance (n = 56). The levels of interferons alfa 2 and gamma, monokine induced by interferon-gamma, interleukin-1α, -1β, -2, -3, -4, -5, -6, -7, -8, -9, -10, -13, -15, -16, -17, -18, interleukin-1 receptor antagonist, interleukin-2 receptor alpha subunits, p40 and p70 subunits of interleukin-12, monocyte chemotactic protein-1, -3, macrophage inflammatory protein-1α, -1β, leukemia inhibitory factor, macrophage ingibitory factor, nerve growth factor beta, stem cell factor, cutaneous T-cell-attracting chemokine, growth-regulated oncogene alpha, hepatocyte growth factor, stem cell growth factor beta, stromal cell-derived factor-1 alfa, interferon gamma inducible protein 10, platelet-derived growth factor-bb, vascular endothelial growth factor, basic fibroblast growth factor, eotaxin, chemokine ligand 5, and macrophage, granulocyte, and granulocyte/macrophage colony-stimulating factors, tumor necrosis factor alfa and beta, and tumor necrosis factor-related apoptosis-inducing ligand were measured with multiplex immunoassay in the blood serum of women at 36–40 weeks of gestation and in the umbilical cord blood serum of their neonates. Results: Cytokine levels varied widely in the both study groups. Women with type 1 diabetes mellitus had higher levels of interleukin-1β, -6, -17, basic fibroblast growth factor, macrophage inflammatory protein-1α, -1β, and lower levels of interleukin-1ra compared to the control group. Their neonates had higher levels of interleukin-6, -8, granulocyte colony-stimulating factor, macrophage inflammatory protein-1α, -1β. Higher levels of interleukin-1β, -6, -17, and basic fibroblast growth factor in the blood serum of the women were associated with time in range less than 70% and the development of diabetic fetopathy. Time in range was inversely associated with the interferon gamma / interleukin-5 (ρ = −0.531; p = 0.013), interferon gamma / interleukin-10 (ρ = −0.441; p = 0.045), interleukin-2 / -10 (ρ = −0.473; p = 0.030), interleukin-1β / -10 (ρ = −0.561; p = 0.008), interleukin-1β / -1ra (ρ = −0.635; p = 0.002), and interleukin-6 / -10 (ρ = −0.540; p = 0.012) ratios. Conclusions: Cytokine profile alterations were the most pronounced in pregnant women with non-target time in range values and in those with diabetic fetopathy development. Serum cytokine levels correlate with glycemic profile parameters but are considered non-specific markers of pregnancy complications.

Fibroblast growth factor 23 and outcomes of atrial fibrillation: from clinical association to genetic evidence.

Fibroblast growth factor 23 (FGF23) has been implicated in the occurrence of atrial fibrillation (AF), but its prognostic value in AF patients remains unclear. A total of 35 197 AF patients with available follow-up data (3.56, 0.47-8.92 years) from the UK Biobank were included. Clinical association between serum FGF23 and AF-related outcomes including mortality, heart failure (HF), ischaemic stroke, and dementia were analysed using multivariable Cox regression. In those passed quality control for array sequencing, polygenic score for FGF23 (PGSFGF23) was calculated as genetic instrument, and the association between PGSFGF23 and the occurrence of endpoints after first AF diagnosis were further explored. In 886 patients who diagnosed AF at or prior to the enrolment, elevated serum FGF23 levels were significantly associated with an increased risk of all-cause (37% increase per standard deviation) and cardiovascular (40% increase per standard deviation) mortality and HF (43% increase per standard deviation). A total of 35 197 patients were available for genetic array sequencing data. Using polygenic score including seven independent SNPs reaching genome-wide significance threshold, genetic association analysis indicated that increased PGSFGF23 is associated with reduced risk of HF but increased risk of all-cause mortality and ischaemic stroke. Our findings suggest that FGF23 is a potential biomarker for accessing AF-related outcomes. The paradoxical association between genetic FGF23 and serum FGF23 level highlights the need for further investigation to elucidate the underlying mechanisms.

Use of FGF-23 and sαKlotho for Risk Stratification in Patients with Acute Heart Failure

Background/Objectives: Soluble αKlotho (sαKlotho) and fibroblast growth factor 23 (FGF-23) are increased in acute heart failure (AHF). This study aimed to assess changes in serum sαKlotho and FGF-23 concentrations during an episode of AHF as well as the usefulness of both biomarkers for predicting long-term prognosis. Methods: The study included 104 consecutive patients hospitalized in t he intensive cardiac care unit due to AHF (mean age, 65.8 ± 14.6 years; mean ejection fraction, 31.4% ± 14). New-onset AHF was reported in 43.3% of the population. Blood samples were measured at entry and on discharge from hospital. The main clinical outcomes assessed in this study were all-cause mortality or rehospitalization due to HF during a 3-year follow-up. Results: At admission sαKlotho, FGF-23, and NT-pro BNP levels, compared with discharge, were significantly higher at p < 0.001, p < 0.001, and p < 0.001 respectively. The 3-year Kaplan–Meier analysis, based on tertiles, revealed, for sαKlotho levels from Tertile 1 on admission and at discharge, a 2-fold higher rate of all-cause mortality or rehospitalization for HF compared with Tertile 3 (p = 0.006 and p = 0.028, respectively). One-third of patients showed an increase in FGF-23 and sαKlotho levels during hospitalization. Patients with the highest percentage increase in the levels of both biomarkers had an elevated risk of all-cause morality or hospitalization for HF (hazard ratio, 2.75; confidence interval, 1.19–6.35; p = 0.02). Conclusions: sαKlotho and FGF-23 levels are elevated during an episode of AHF. Low sαKlotho levels are associated with an increased risk of all-cause mortality or rehospitalization for HF. Increases in sαKlotho and FGF-23 values during hospitalization identify patients with poor prognosis.

Glucose Metabolic Abnormalities and Their Interaction With Defective Phosphate Homeostasis in Tumor-induced Osteomalacia.

Phosphate homeostasis was compromised in tumor-induced osteomalacia (TIO) due to increased fibroblast growth factor 23 (FGF23) secretion. Nevertheless, the glucose metabolic profile in TIO patients has not been investigated. This work aimed to clarify the glucose metabolic profiles in TIO patients and explore their interaction with impaired phosphate homeostasis. 20 TIO patients, 20 individuals with normal glucose tolerance, and 20 patients with type 2 diabetes mellitus (DM) were enrolled and underwent an oral glucose tolerance test (OGTT). Serum phosphate and FGF23 concentration were monitored during OGTT. In patients with TIO, 60% (12/20) exhibited impaired glucose tolerance (IGT) and 5% (1/20) had type 2 DM. Those with IGT or type 2 DM experienced more ambulatory difficulties (69.2% vs 42.9%), lower phosphate concentrations (0.43 ± 0.10 vs 0.53 ± 0.10, P = .042), and lower calcium concentrations (2.20 ± 0.08 vs 2.30 ± 0.40, P = .001) compared to TIO patients without these conditions. According to correlation analysis, serum phosphate levels were negatively correlated with plasma glucose levels at 60 minutes (P < .001), fasting plasma insulin levels (P < .05), and homeostasis model assessment for insulin resistance (P < .05). Those with high FGF23 levels had a higher glucose level at 60 minutes (10.5 [9.3, 12.3] vs 7.3 [6.4, 10.1], P = .048) than that of low group. After glucose loading, both FGF23 and phosphate levels exhibited a decreasing trend. The development of diabetes in TIO patients may be predisposed by ambulatory issues, low phosphate, and elevated FGF23 levels. Dysglycemia might further aggravate hypophosphatemia.

Risk factors for radial artery calcification in patients with and without uremia

BackgroundCalcification of the radial artery is one of the main causes of anastomotic stenosis in autogenous arteriovenous fistulas in uremic patients. However, the pathogenesis of calcification is still unknown. This study attempted to screen and validate the risk factors for vascular calcification in patients with uremia.MethodsSerum of blood were collected and tissue samples from radial artery were obtained from 60 uremia patients with or without hemodialysis. General biochemical indicators and calcification-related molecules were collected and detected via ELISA or correlation analysis. In addition, pathological changes and calcification-related molecules in the radial artery were evaluated by HE or immunohistochemical staining.ResultsThere were differences in total calcium, calcium-phosphorus products, allograft inflammatory factor 1 (AIF-1), intact parathyroid hormone (iPTH), vitamin D (VD), fibroblast growth factor 23 (FGF23) and soluble klotho (sKlotho) in the blood of uremic patients with or without hemodialysis. Furthermore, these factors are related to calcification of the radial artery. The expression of AIF-1, PTHR1, VDR, FGF23 and sKlotho was also increased in the calcified radial artery.ConclusionsThe levels of AIF-1, PTH, VDR, FGF23 and sKlotho in serum were associated with calcification of the radial artery in patients with uremia. Furthermore, calcification of the radial artery was further aggravated by abnormalities in calcium and phosphorus in maintenance hemodialysis patients.

Primary Hyperparathyroidism-Phosphaturic Mesenchymal Tumour: An Unusual Association and a Probable Syndrome

Phosphaturic Mesenchymal Tumour (PMT) is a rare and underdiagnosed tumour that causes Tumour-Induced Osteomalacia (TIO). These tumours produce Fibroblast Growth Factor-23 (FGF23), which inhibits renal tubular phosphate reabsorption, leading to hyperphosphaturia and oncogenic osteomalacia. The association of primary Hyperparathyroidism (pHPT) with PMT is extremely rare, with only two cases reported in the literature to date. A 51-year-old male presented in a bedridden state with multiple episodes of fractures throughout his skeleton over six years. Investigations revealed mild hypocalcaemia, marked hypophosphatemia, elevated serum Alkaline Phosphatase (ALP), low 25-Hydroxy Vitamin D, and persistently raised Parathormone (PTH) levels. A 68-Ga-DOTANOC 3D PET (Positron Emission Tomography) scan revealed a 4.1×3.2×2.5 cm DOTA avid mass in the right thigh. FGF23 levels were found to be 1466 pg/mL. A diagnosis of hypophosphatemic osteomalacia with pHPT was made, and the mass was subsequently excised. The thigh mass measured 3.5×2.5 cm and had a tan-brown cut surface. Microscopy revealed a benign spindle cell tumour with a vasoformative pattern and areas of grungy calcification. Immunohistochemistry demonstrated strong positivity for Vimentin, while CD34, CD68, CK, and Desmin were negative. A diagnosis of PMT, Mixed Connective Tissue type, was established. Normal phosphate, calcium, and FGF23 levels were restored after surgery, and the patient was able to walk again. This unusual case of a patient with pHPT and PMT, and the possible existence of a “pHPT-PMT syndrome, “was reported in the Times of India on November 20, 2022, as “Rare phosphorus-guzzling tumour left Dongri man bedridden for three years.” The exact aetiology for the association of PMT and pHPT is not known, and the hypothesis of aberrant gene expression has been implicated.

Nivoi galektina-3 u serumu i faktora rasta fibroblasta-23 u odnosu na dijabetes tip 2 i kardiovaskularni rizik

Background: The clinical utility of galectin-3 and fibroblast growth factor 23 (FGF-23) needs to be further explored since previous studies show divergent results in relation to type 2 diabetes (T2D) and cardiovascular risk. Hence, the aim of this research was to explore galectin-3 and FGF-23 in relation to T2D, as well as to examine the potential association of these biomarkers with atherosclerotic cardiovascular disease (ASCVD) risk score in Montenegrin adults. Methods: A total of 35 T2D patients and 36 controls were consecutively enrolled. Serum galectin-3 and FGF-23 were determined by ELISA. The ASCVD risk score was calculated. Results: Higher serum galectin-3 levels were shown in T2D patients (p=0.016) in comparison with the control group. The increase in galectin-3 levels for 1 ng/mL showed an 8.5% higher probability of T2D occurrence (OR=1.085, p=0.015). FGF-23 levels did not differ between the control and the T2D group. Serum galectin-3 correlated with FGF23 (r=0.390, p=0.001). Both galectin-3 (r=0.306, p=0.010) and FGF-23 (r=0.332, p=0.005) correlated with ASCVD risk score in bivariate Spearman's correlation analysis, but these correlations were not retained in binary logistic regression analysis. Conclusions: Serum galectin-3 levels but not FGF-23 are higher in T2D patients. Serum galectin-3 correlated with FGF-23. Although both biomarkers were correlated with the ASCVD risk score, further statistical analysis did not confirm their independent associations with cardiovascular risk. Studies with a large sample size are needed to further explore this issue.

Hemodiafiltration with endogenous reinfusion for uremic toxin removal in patients undergoing maintenance hemodialysis: a pilot study

Objective To delineate the efficacy and safety profile of hemodiafiltration with endogenous reinfusion (HFR) for uremic toxin removal in patients undergoing maintenance hemodialysis (MHD). Methods Patients who have been on MHD for a period of at least 3 months were enrolled. Each subject underwent one HFR and one hemodiafiltration (HDF) treatment. Blood samples were collected before and after a single HFR or HDF treatment to test uremic toxin levels and to calculate clearance rate. The primary efficacy endpoint was to compare uremic toxin levels of indoxyl sulfate (IS), λ-free light chains (λFLC), and β2-microglobulin (β2-MG) before and after HFR treatment. Secondary efficacy endpoints was to compare the levels of urea, interleukin-6 (IL-6), P-cresol, chitinase-3-like protein 1 (YKL-40), leptin (LEP), hippuric acid (HPA), trimethylamine N-oxide (TMAO), asymmetric dimethylarginine (ADMA), tumor necrosis factor-α (TNF-α), fibroblast growth factor 23 (FGF23) before and after HFR treatment. The study also undertook a comparative analysis of uremic toxin clearance between a single HFR and HDF treatment. Meanwhile, the lever of serum albumin and branched-chain amino acids before and after a single HFR or HDF treatment were compared. In terms of safety, the study was meticulous in recording vital signs and the incidence of adverse events throughout its duration. Results The study enrolled 20 patients. After a single HFR treatment, levels of IS, λFLC, β2-MG, IL-6, P-cresol, YKL-40, LEP, HPA, TMAO, ADMA, TNF-α, and FGF23 significantly decreased (p < 0.001 for all). The clearance rates of λFLC, β2-MG, IL-6, LEP, and TNF-α were significantly higher in HFR compared to HDF (p values: 0.036, 0.042, 0.041, 0.019, and 0.036, respectively). Compared with pre-HFR and post-HFR treatment, levels of serum albumin, valine, and isoleucine showed no significant difference (p > 0.05), while post-HDF, levels of serum albumin significantly decreased (p = 0.000). Conclusion HFR treatment effectively eliminates uremic toxins from the bloodstream of patients undergoing MHD, especially protein-bound toxins and large middle-molecule toxins. Additionally, it retains essential physiological compounds like albumin and branched-chain amino acids, underscoring its commendable safety profile.

Role of serum fibroblast growth factor-23 and Klotho level in COVID-19 infection-related mortality: a prospective study.

This study investigated the role of fibroblast growth factor 23 (FGF23)/Klotho in the mortality of patients hospitalized with coronavirus disease 2019 (COVID-19), excluding those with chronic kidney disease (CKD). A prospective cross-sectional study was conducted from April 2021 to May 2022. Patients who tested positive for COVID-19 via polymerase chain reaction and were hospitalized, were classified into two groups (survivors and non-survivors) at the end of their hospital follow-up. Demographic data, clinical status, and prognosis were analyzed. A total of 66 patients (age 58.8 ± 17.0 years, 60.6% male) were included. The mean age of non-survivors (67.2 ± 1 years) was significantly higher than the survivors (49.2 ± 1 years; p < 0.0001). FGF23 was significantly elevated in non-survivors (301 ± 20 pg/mL), compared to survivors (160 ± 36 pg/mL; p < 0.0001). Factors with significant differences (p < 0.001) between the two groups were investigated as independent mortality predictors using logistic regression analysis. FGF23 (p = 0.01), age (p = 0.045), and oxygen saturation at admission (p = 0.02) were independent predictors of mortality. High serum FGF23 levels were associated with COVID-19-related mortality; Klotho levels were lower (p = 0.028). Vitamin D was not significantly different between the groups. Elevated serum FGF23 and parathyroid hormone (PTH), and lower Klotho levels, were associated with COVID-19-related mortality in patients without CKD. There was no association with serum vitamin D levels. Further studies are required to establish the relationship between mortality and FGF23/Klotho, PTH, and vitamin D levels.

Comprehensive Metabolomic Profiling in Adults with X-Linked Hypophosphatemia: A Case-Control Study.

X-linked hypophosphatemia (XLH) is a rare disorder characterized by elevated levels of fibroblast growth factor 23 (FGF-23), leading to hypophosphatemia and complications in diagnosis due to its clinical heterogeneity. Metabolomic analysis, which examines metabolites as the final products of cellular processes, is a powerful tool for identifying in vivo biochemical changes, serving as biomarkers of pathological abnormalities, and revealing previously uncharted metabolic pathways. A multicenter cross-sectional case-control study of adult patients diagnosed with XLH was conducted. Serum metabolomic analysis was performed with an Ultra-Performance Liquid Chromatography equipment (UPLC) coupled to a high-resolution mass spectrometer (MS). An analysis of metabolic pathways using MetaboAnalyst version 5.0 and a quantitative enrichment analysis (QEA) was performed. We employed multivariate statistical models, including a principal component analysis (PCA) and an orthogonal partial least squares discriminant analysis (OPLS-DA) regression model. A cohort of 20 XLH patients and 19 control subjects were recruited. A total of 104 metabolites were identified. The differential metabolites identified included glycine, taurine, hypotaurine, phosphoethanolamine, pyruvate, guanidoacetic acid, serine, succinate, 2-aminobutyric acid, glutamine, 2-hydroxyvaleric acid, methionine, ornithine, phosphorylcholine, hypoxanthine, lysine, and N-methylnicotinamide. Enrichment analysis identified disturbances in key metabolic pathways, including phosphatidylethanolamine biosynthesis, sphingolipid metabolism, and phosphatidylcholine biosynthesis. Additionally, pathways related to cysteine metabolism, glycolysis, and pyruvate metabolism. This study identified significant differences in the metabolic profiles of individuals with XLH compared to healthy controls. These findings enhance understanding of potential pathogenic mechanisms and offer a metabolic basis for further in-depth investigations into XLH.

Glycerol-3-phosphate contributes to the increase in FGF23 production in chronic kidney disease.

Why fibroblast growth factor 23 (FGF23) levels increase markedly in chronic kidney disease (CKD) is unknown. Recently, we found that phosphate stimulates renal production of glycerol-3-phosphate (G-3-P), which circulates to the bone to trigger FGF23 production. To assess the impact of G-3-P on FGF23 production in CKD, we compared the effect of adenine-induced CKD in mice deficient in glycerol-3-phosphate dehydrogenase 1 (Gpd1), an enzyme that synthesizes G-3-P, along with wild-type littermates. We found that an adenine diet causes a similar degree of renal insufficiency across genotypes and that adenine-induced CKD increases blood G-3-P and FGF23 levels in wild-type mice. Furthermore, we found that the increases in both G-3-P and FGF23 are significantly attenuated, but not fully abrogated, in Gpd1-/- compared with Gpd1+/+ mice with CKD. There is no difference in blood phosphate or parathyroid hormone between Gpd1-/- and Gpd1+/+ mice on an adenine diet, but adenine-induced CKD causes greater cortical bone loss in Gpd1-/- mice. In a separate cohort of rats fed an adenine or control diet, we confirmed that CKD causes an increase in blood G-3-P levels. Importantly, an acute phosphate load increases G-3-P production in both CKD and non-CKD rats, with a significant correlation between measured kidney phosphate uptake and blood G-3-P levels. Together, these findings establish a key role for G-3-P in mineral metabolism in CKD, although more work is required to parse the factors that regulate both Gpd1-dependent and Gpd1-independent G-3-P production in this context.NEW & NOTEWORTHY This study shows that glycerol-3-phosphate, a glycolytic by-product recently implicated in a kidney-to-bone signaling axis that regulates FGF23 production, increases in mice and rats with CKD. Furthermore, mice deficient in a key enzyme that synthesizes glycerol-3-phosphate have attenuated increases in both glycerol-3-phosphate and FGF23 in CKD, along with enhanced cortical bone loss. These studies identify glycerol-3-phosphate as a novel regulator of FGF23 and mineral metabolism in CKD.

Inflammatory proteins and hidradenitis suppurativa: Insights from genetic correlation and Mendelian randomization.

Previous research has highlighted a significant association between inflammatory proteins and the development and progression of hidradenitis suppurativa (HS). Nevertheless, the potential causative link between these factors remains to be definitively established. To investigate the genetic correlation between inflammatory proteins and HS, linkage disequilibrium score regression (LDSC) was employed. Mendelian randomization (MR) analysis, incorporating inverse variance weighted, MR-Egger, and weighted median methodologies, was utilized to evaluate the possible causal relationship between circulating inflammatory proteins (CIPs) and HS. Additionally, reverse MR analysis was carried out to explore reverse causality. The data set for 91 CIPs was derived from a genome-wide protein quantitative trait loci study, while HS-related data were acquired from the FinnGen study. Moreover, the stability of the causal relationships was assessed via sensitivity analyses, encompassing tests for pleiotropy, heterogeneity, and leave-one-out analysis. The LDSC analysis suggested the existence of genetic correlations between the levels of Fibroblast growth factor 21 (FGF-21), stem cell factor, and HS. The MR analysis identified a suggestive association of T-cell surface glycoprotein CD5 and C-X-C motif chemokine 11 with an elevated risk of HS. Conversely, C-C motif chemokine 4, Protein S100-A12, Interleukin-10 receptor subunit beta, and Programmed cell death 1 ligand 1 were associated with a diminished risk of HS. Moreover, HS was demonstrated to increase the levels of four CIPs: Interleukin-20, Leukemia inhibitory factor (LIF), LIF receptor, and Thymic stromal lymphopoietin. The findings of this investigation offer suggestive evidence for possible genetic correlations and causal links between various genetically predicted inflammatory proteins and HS. There exists a pressing requirement for additional studies to elucidate the fundamental processes driving these associations.

Analysis of Fibroblast Growth Factor 2 Impact and Mechanism on Broncho-Pulmonary Dysplasia

Objective: Epithelial-mesenchymal transition (EMT) of alveolar epithelial cells is an important mechanism for the onset and development of broncho-pulmonary dysplasia (BPD). Fibroblast growth factor 2 (FGF2) is involved in the development and repair of injury in many organs, particularly the lung. The role of FGF2 in BPD is currently unclear. The aim of our study was to investigate the expression of FGF2 in lung tissue of BPD mice, to further clarify the effect of FGF2 on EMT in alveolar epithelial cells and to actively search for possible signaling pathways. Methods: The BPD model was induced by exposure to hyperoxia. Lung tissue samples were collected and hematoxylin and eosin staining was used to determine the modeling effect. Quantitative real-time polymerase chain reaction (QRT-PCR), immunohistochemistry was used to detect FGF2 expression in BPD mice. To further investigate the effect of FGF2 supplementation and deficiency on EMT in alveolar epithelial cells, A549 cells were cryopreserved, resuspended, cultured, and passaged. Transforming growth factor-β1 (TGF-β1) was used to induce EMT. FGF2 small interfering RNA fragments were synthesized and screened. Fibroblast growth factor receptor 1 (FGFR1) expression was inhibited by BGJ398. (3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium) (MTS) assay was used to detect the effect of FGF2 and infigratinib (BGJ398) on cell proliferation. We used qRT-PCR and Western blot to detect the expression of epithelial cell markers, mesenchymal cell markers and EMT-related signaling pathway proteins. Results: Our results showed that the successful established hyperoxia mice model were characteristic by BPD. Hyperoxia decreased FGF2 on day 4, upregulated FGF2 on day 21, which resulted in EMT. In vitro, we found that FGF2 alone increased the expression of mesenchymal markers, decreased the expression of epithelial markers and activated phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), small mother against decapentaplegic (Smad), mitogen-activated protein kinase (P38), and extracellular signal-regulated kinase (ERK) signaling pathways. FGF2 could not reverse but synergistically promote Transforming growth factor-β1 (TGF-β1)-induced EMT of alveolar epithelial cells. Silencing FGF2 increased the expression of epithelial marker E-cadherin, inhibited the PI3K/AKT, Smad, and P38 signaling pathways activated by TGF-β1, but activated ERK signaling. FGF2 receptor inhibitor BGJ398 reversed TGF-β1-induced EMT, decreased the expression of FGFR1, and inhibited ERK signaling pathway activation. Conclusions: FGF2 was closely associated with EMT in BPD mice. Both high and low levels of FGF2 promoted EMT in A549. The FGF2 receptor inhibitor BGJ398 reversed TGF-β1-induced EMT in A549 by inhibiting the FGFR1/P-ERK signaling pathway.

Heparan sulfate regulates the fate decisions of human pluripotent stem cells.

Heparan sulfate (HS) is an anionic polysaccharide generated by all animal cells, but our understanding of its roles in human pluripotent stem cell (hPSC) self-renewal and differentiation is limited. We derived HS-deficient hPSCs by disrupting the EXT1 glycosyltransferase. These EXT1-/- hPSCs maintain self-renewal and pluripotency under standard culture conditions that contain high levels of basic fibroblast growth factor(bFGF), a requirement for sufficient bFGF signaling in the engineered cells. Intriguingly, Activin/Nodal signaling is also compromised in EXT1-/- hPSCs, highlighting HS's previously unexplored involvement in this pathway. As a result, EXT1-/- hPSCs fail to differentiate into mesoderm or endoderm lineages. Unexpectedly, HS is dispensable for early ectodermal differentiation of hPSCs but still critical in generating motor neurons. Those derived from HS-deficient hPSCs lack proper neuronal projections and show alterations in axonogenesis gene expression. Thus, our study uncovers expected and unexpected mechanistic roles of HS in hPSC fate decisions.

The Effect of Ferric Carboxymaltose on Fibroblast Growth Factor 23 (FGF23) in Children with Iron Deficiency Anemia Due to Gastrointestinal Diseases

Background: Hypophosphatemia is a known side-effect of parenteral iron administration, especially after intravenous ferric carboxymaltose (FCM). Fibroblast growth factor 23 (FGF23) is thought to play an important role in the pathophysiology of serum phosphate homeostasis. This study aimed to investigate the effects of FCM on FGF23 serum levels in FCM-treated pediatric patients with iron deficiency (ID)/iron deficiency anemia (IDA) caused by gastrointestinal diseases. Methods: Over 30 months, FGF23 serum levels were assessed prospectively in children with ID/IDA due to gastrointestinal diseases and treated with FCM infusion. Serum levels of intact FGF23 (iFGF23) were assessed and correlated to phosphate serum levels and factors of bone metabolism. Blood sampling was performed in three phases: before FCM infusion, 7–10 days after FCM infusion, and 6–8 weeks after FCM infusion. Results: A total of 42 FCM infusions were given to 35 children (20 girls) with a mean age (±SD) of 12.2 (±4.03) years (range: 2–16 years). The median levels of iFGF23 did not show a significant difference across the three phases (p = 0.56). No significant correlation was found between iFGF23 levels and 25-hydroxyvitamin D/parathyroid hormone/serum phosphate/serum calcium/alkaline phosphatase. No significant change was noted between pre- and post-treatment serum phosphate levels. However, four children (11.42%) developed asymptomatic and transient hypophosphatemia. Conclusions: No significant difference was found between pre-and post-FCM infusion serum iFGF23 levels and bone metabolism parameters. An increase of iFGF23 serum levels 7–10 days after FCM infusion was noted in patients with hypophosphatemia.

Controlled dietary phosphate loading in healthy young men elevates plasma phosphate and FGF23 levels.

Increased dietary inorganic phosphate (Pi) intake stimulates renal Pi excretion, in part, by parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23) or dopamine. High dietary Pi may also stimulate sympathetic outflow. Rodent studies provided evidence for these regulatory loops, while controlled experiments in healthy humans examined periods of either a few hours or several weeks, and often varied dietary calcium intake. The effects of controlled, isolated changes in dietary Pi intake over shorter periods are unknown. We studied the effects of a low or high Pi diet on parameters of mineral metabolism in 10 healthy young men. Participants received a standardized diet (1000mg phosphorus equivalent/day) supplemented with either a phosphate binder (low Pi diet) or phosphate capsules (750mg phosphorus, high Pi diet) in a randomized cross-over trial for 5days with a 7-day washout between diets. High Pi intake increased plasma Pi levels and 24-h excretion and decreased urinary calcium excretion. High Pi intake increased intact FGF23 (iFGF23) and suppressed plasma Klotho without affecting cFGF23, PTH, calcidiol, calcitriol, Fetuin-A, dopamine, epinephrine, norepinephrine, metanephrine, or aldosterone. Higher iFGF23 correlated with lower calcitriol and higher PTH. These data support a role for iFGF23 in increasing renal Pi excretion and reducing calcitriol in healthy young men during steady-state high dietary Pi intake. High dietary Pi intake elevated blood Pi levels in healthy young subjects with normal renal function and may therefore be a health risk, as higher serum Pi levels are associated with cardiovascular risk in the general population.

Poly-D,L-Lactic Acid Fillers Increase Subcutaneous Adipose Tissue Volume by Promoting Adipogenesis in Aged Animal Skin.

During aging, subcutaneous white adipose tissue (sWAT) thickness and the adipogenic potential of adipose-derived stem cells (ASCs) decline. Poly-D,L-lactic acid (PDLLA) fillers are commonly used to restore diminished facial volume. Piezo1 increases polarizing macrophages towards the M2 phenotype, which promotes the secretion of fibroblast growth factor 2 (FGF2), thereby increasing ASC survival. This study evaluated whether PDLLA enhances adipogenesis in ASCs by modulating M2 polarization in an in vitro senescence model and in aged animals. Lipopolysaccharide (LPS)-induced senescent macrophages showed decreased Piezo1, which was upregulated by PDLLA. CD163 (an M2 marker) and FGF2 were downregulated in senescent macrophages but were upregulated by PDLLA. We evaluated whether reduced FGF2 secretion from senescent macrophages affects ASCs by applying conditioned media (CM) from macrophage cultures to ASCs. CM from senescent macrophages decreased ERK1/2 and proliferation in ASCs, both of which were restored by CM from PDLLA-stimulated senescent macrophages. Adipogenesis inducers (PPAR-γ and C/EBP-α) were downregulated by CM from senescent macrophages but upregulated by CM from PDLLA-stimulated senescent macrophages in ASCs. Similar patterns were observed in aged animal adipose tissue. PDLLA increased Piezo1 activity, M2 polarization, and FGF2 levels. PDLLA also enhanced ERK1/2, cell proliferation, PPAR-γ, and C/EBP-α expression, leading to increased adipose tissue thickness. In conclusion, our study showed that PDLLA increased adipose tissue thickness by modulating adipogenesis.

Association of Fibroblast Growth Factor 23 and Cardiac Mechanics in the Cardiovascular Health Study.

Elevated levels of fibroblast growth factor 23 (FGF23) are associated with left ventricular hypertrophy and heart failure (HF) in individuals with and without kidney disease. Prior studies investigated the association of FGF23 and structural cardiac changes using conventional echocardiography, which is limited in its ability to detect early cardiac dysfunction. We investigated the relationship between FGF23 levels and cardiac dynamics using two-dimensional speckle tracking echocardiography (2D-STE), a novel imaging modality. This was a cross-sectional analysis of data from the Cardiovascular Health Study, an ongoing prospective, population-based cohort study. The study population included 506 participants from CHS with available c-terminal (cFGF23) and intact FGF23 (iFGF23) measurements from 1996-1997 and 2D-STE images from 1994-1995. Forty two percent of the study population had CKD, defined as an eGFR < 60 ml/min/1.73m2, and the mean eGFR was 63 ml/min/1.73m2. The primary exposures were cFGF23 and iFGF23. The primary outcomes were six 2D-STE parameters performed at the 1994-1995 study visit. Linear regression models were used to examine the independent associations of FGF23 with six cardiac 2D-STE indices adjusting for demographics, cardiovascular risk factors, markers of kidney disease severity, and inflammation. cFGF23 levels were moderately correlated with iFGF23 levels in the CHS population. In fully adjusted models, cFGF23 was associated with left atrial dysfunction, but no other cardiac imaging parameter (β estimate -2.47; 95% Confidence Interval -4.68, -0.25; Table 2). iFGF23 was not associated with any of the six 2D-STE indices. Limitations include small sample size and noncurrent FGF23 measurements and 2D-STE imaging. In a limited sample of individuals enrolled in the CHS with c- and i-FGF23 measurements, we did not find consistent associations between FGF23 levels and 2D-STE parameters. Further investigations in a larger population with concurrent 2D-STE are needed to better understand the associations of FGF23 with early changes in cardiac mechanics.