Fibroblast Growth Factor 23 Research Articles

Fibroblast growth factor 23 as a risk factor for incident diabetes.

Diabetes is a major global health concern, affecting millions and increasing morbidity and mortality. Recent research highlights fibroblast growth factor 23 (FGF23) as a potential contributor to type 2 diabetes and its cardiovascular complications. This review explores the role of FGF23 in metabolic and cardiovascular dysfunction and discusses possible therapeutic interventions. Deregulated FGF23 is linked to insulin resistance, pancreatic β-cell dysfunction, and systemic inflammation. Studies suggest FGF23 influences glucose metabolism via insulin signaling, oxidative stress, and inflammation. Epidemiological data indicate that elevated FGF23 levels are associated with an increased risk of type 2 diabetes and posttransplant diabetes, independent of traditional risk factors. Higher FGF23 levels have also been linked with an increased cardiovascular risk in patients with diabetes, even without chronic kidney disease. FGF23 is emerging as a key factor in the cardiovascular-kidney-metabolic syndrome, connecting diabetes and cardiovascular disease. While studies suggest consistent associations, causal mechanisms remain unclear. No therapies specifically target FGF23 to lower diabetes risk, but fibroblast growth factor receptor 4 (FGFR4) inhibitors show promise. Future research should examine the role of FGF23 in individuals with normal kidney function and explore whether modifying its levels could reduce diabetes and cardiovascular risk.

Shuangshi Tonglin Capsule Improves Prostate Fibrosis through Nrf2/TGF-β1 Signaling Pathways.

To investigate the effect and mechanism of Shuangshi Tonglin Capsules (SSTL) in the treatment of prostate fibrosis (PF). Human prostate stromal cells (WPMY-1) were used for in vitro experiments to establish PF cell models induced with estradiol (E2). The cell proliferation, migration and clonogenic capacity were determined by cell counting kit-8, scratch assay, and crystal violet staining, respectively. Sprague-Dawley rats were used for in vivo experiments. The changes in histomorphology and organ index of rat prostate by SSTL were determined. Pathologic changes and collagen deposition changes in rat prostate were observed by haematoxylin and eosin (HE) and Masson staining. Enzyme-linked immunosorbent assay kits were used to determine changes in rat PF markers fibroblast growth factor-23 (FGF-23), E2 and prostate specific antigen (PSA). Mechanistically, changes in oxidative stress indicators by SSTL were determined in WPMY-1 cells and PF rats. Then the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) and transforming growth factor-β1 (TGF-β1)/Smad pathway-related proteins as well as Nrf2 and TGF-β1 mRNA were further detected by Western blot or quantitative real-time polymerase chain reaction both in vivo and in vitro. In the efficacy study, SSTL significantly reduced the proliferation, migration, and clonogenic ability of cells, improved the morphology of the glandular tissue, significantly reduced the prostate index, reduced glandular fibrous tissue and collagen deposition, and resulted in a significant decrease in the levels of FGF-23, E2 and PSA (P<0.01 or P<0.05). In the mechanistic study, SSTL ameliorated oxidative stress by significantly increasing superoxide dismutase and glutathione peroxidase levels and decreasing malondialdehyde level in WPMY-1 cells and rats (P<0.01 or P<0.05). SSTL significantly elevated the expressions of Nrf2, HO-1, NAD(P)H quinone oxidoreductase 1 (NQO-1), and Smad7 proteins in both cells and rats, and significantly decreased the expressions of TGF-β1, collagen I, α-smooth muscle actin and Smad4 proteins (P<0.01 or P<0.05). SSTL also elevated the content of Nrf2 mRNA and decreased the content of TGF-β1 mRNA in cells and rats (P<0.01 or P<0.05). The Nrf2 inhibitor ML385 was added in in vitro experiments to further validate the pathway relevance. SSTL was effective in improving PF in vivo and in vitro, and its mechanism of action may function through the Nrf2/TGF-β1 signaling pathway.

Unveiling the mystery: A rare case of hypophosphatemia

Tumor-induced osteomalacia (TIO) or oncogenic osteomalacia is a rare paraneoplastic syndrome characterized by an autonomous and unregulated production of fibroblast growth factor 23 (FGF23), which promotes urinary phosphorus wasting and systemic hypophosphatemia. Clinical manifestations are often nonspecific and unfortunately, the syndrome is underdiagnosed or recognized late. Hypophosphatemia is often attributed to other more common etiologies and is often not identified at all, leading to a more advanced disease at the time of diagnosis. Thus, it is necessary to have a high index of suspicion when evaluating hypophosphatemia, as early identification and intervention of TIO can prevent or reverse osteomalacia and lead to an expedited investigation of a culprit neoplasm. We describe a case of TIO associated with established mesothelioma and outline the diagnostic steps taken that ultimately taken to reach a final diagnosis. While rare, this condition should not be missed by the conventional nephrologist, who routinely measures phosphorus levels in their patients, and thus, we provide a framework to follow in the assessment of hypophosphatemia and the ultimate diagnosis of TIO.

BIOMARKERS IN THE EARLY DIAGNOSIS OF ACUTE KIDNEY INJURY IN CHILDREN (LITERATURE REVIEW)

The diagnosis of acute kidney injury (AKI) is one of the most pressing issues in modern pediatrics. The classical method of diagnosing AKI is to determine the level of glomerular filtration rate, serum creatinine and diuresis. In the last 10-15 years, an active search and research of new biomarkers (BM) of acute kidney injury has been conducted. Aim of the study. To increase the awareness of pediatricians about the possibilities of using biomarkers in the early diagnosis and timely treatment of AKI in children based on the analysis of current literature. Materials and methods. A search of modern literature sources on medical portals such as UpToDate, PubMed, etc. on the use of BM in the early diagnosis of AKI in pediatric patients was performed. The data obtained were reviewed and analyzed. The results. The article presents a review of the current literature on the possibilities of using biomarkers of AKI in children in the early diagnosis of this pathology. Among the biomarkers of AKI are the following creatinine, urea, lipocalin associated with neutrophil gelatinase (NGAL); cystatin C, fractional solute excretion (FeS), ammonium (NH4)/ammonia (NH3), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), tissue inhibitor of metalloproteinase-2 (TIMP-2); insulin-like growth factor binding protein 7 (IGFBP 7); hepatic fatty acid binding protein (L-FABP); soluble urokinase plasminogen activator receptor (suPAR), Dickkopf 3 (DKK3), monocyte chemotactic peptide-1 (MCP-1), epidermal growth factor (EGF), fibroblast growth factor-23 (FGF-23), chemokine ligand 14 (CCL14), chitinase-3-like protein-1 (CHI3L1), uromodulin (Tamm-Horsfall protein), and α1-microglobulin (α1-M). Most of these AKI BMs are not widely used in daily clinical practice and require further investigation, making it prudent to increase the number of studies in this area. Conclusions. The presented materials will help to raise awareness among pediatricians and pediatric nephrologists about the possibilities of using modern biomarkers of AKI in children and expand the prospects for early diagnosis of this pathology, which will ensure the ability to detect the development of this syndrome in time and start effective treatment.

Dissecting causal relationships between gut microbiota, inflammatory factors, and acute kidney injury: A Mendelian randomization study.

Acute kidney injury (AKI) is common in critically ill patients in the medical intensive care unit (ICU), and it is associated with increased morbidity and mortality. Recent studies suggest a significant link between AKI and disturbances in the gut microbiota (GM). We used summary genome-wide association studies (GWAS) data from MiBioGen for GM and AKI data from the FinnGen cohort. Causal relationships were primarily assessed using the inverse variance weighted (IVW) method, with MR-PRESSO and MR-Egger tests to address potential horizontal pleiotropy. Heterogeneity was evaluated using Cochran's Q and I2 values. The IVW method revealed a causal association between 14 gut microbial taxa and AKI. The Phylum Firmicutes (id. 1672), Order Pasteurellales (id. 3688), Genus unknowngenus (id. 2071), Genus RuminococcaceaeUCG010 (id. 11367), Genus RuminococcaceaeUCG005 (id. 11363), Genus Haemophilus (id. 3698), Genus Flavonifractor (id. 2059), Genus ErysipelotrichaceaeUCG003 (id. 11384), Genus Dialister (id. 2183), Genus Coprococcus2 (id. 11302), and Family Pasteurellaceae (id. 3689) were negatively associated with AKI risk. Conversely, Genus Victivallis (id. 2256), Genus RuminococcaceaeUCG013 (id. 11370), and Genus Erysipelatoclostridium (id. 11381) were positively associated with AKI risk. Additionally, hepatocyte growth factor (HGF), interleukin-10 (IL-10), fibroblast growth factor-23 (FGF-23), and tumor necrosis factor alpha (TNF-α) were potentially causative in AKI onset. This study emphasizes the significant role of gut microbiota interactions with inflammatory factors in AKI pathogenesis. The identified risk factors underscore their essential role in both the onset and progression of AKI.

The vitamin D3 hormone, 1,25(OH)2D3, regulates fibroblast growth factor 23 (FGF23) production in human skin cells.

The bone hormone fibroblast growth factor 23 (FGF23) regulates renal phosphate reabsorption and the enzymatic production of active vitamin D3 (1,25(OH)2D3). Therefore, FGF23 production in bone cells is closely regulated by 1,25(OH)2D3 acting via the vitamin D receptor (VDR). Skin cells can produce hydroxyvitamin D3 metabolites from its precursor D3 made through UVB-light exposure. Interestingly, expression of Fgf23 has been found in rodent skin, but its expression, regulation, and role in human skin are unclear. Therefore, we investigated whether hydroxyvitamin D3 metabolites regulate FGF23 in human skin cells. Primary adult and neonatal epidermal keratinocytes (HEKn), melanocytes (HEMn), dermal fibroblasts (HDFn), as well as human melanoma cells, HaCaT, HaCaT VDR KO, and A431 epidermoid cells, were used to assess FGF23 gene expression (qRT-PCR), cellular FGF23 protein (western blot), or secreted FGF23 protein (ELISA) after treatment with hydroxyvitamin D3 metabolites. HaCaT cells treated with recombinant FGF23 were used to explore its function in skin. Human skin cells can synthesize FGF23. Treatment with 1,25(OH)2D3 significantly increased FGF23 mRNA levels in HaCaT and HDFn cells, and moderately in HEKn cells, mediated in part by the VDR. It also moderately enhanced mRNA levels of the FGF23-processing enzyme GALNT3 and stimulated secretion of hormonally active FGF23 from HaCaT cells. Treatment of HaCaT cells with FGF23 increased mRNA levels of the cholesterol-and vitamin D-metabolizing enzymes, CYP11A1 and CYP27A1. In conclusion, human skin cells express and secrete FGF23, which is regulated by 1,25(OH)2D3 acting in part by the VDR. FGF23 affects the expression of cutaneous sterol-metabolizing enzymes.

Dynamic single cell transcriptomics defines kidney FGF23/KL bioactivity and novel segment-specific inflammatory targets.

Dynamic single cell transcriptomics defines kidney FGF23/KL bioactivity and novel segment-specific inflammatory targets.

Osteosarcopenia in Chronic Kidney Disease: An Overlooked Syndrome?

Healthy ageing relies on maintaining physiological systems, particularly the musculoskeletal system (MKS). After 50, declines in bone density, muscle mass and strength increase the risk of osteoporosis and sarcopenia, leading to frailty, fractures and higher healthcare costs. Osteosarcopenia, combining osteoporosis and sarcopenia, is rising because of the ageing population. Chronic kidney disease (CKD) exacerbates this condition through disruptions in mineral metabolism, hormonal imbalances and inflammation, further compromising musculoskeletal health. This review examines the pathophysiology of osteosarcopenia associated with CKD, focusing on the role of mineral and hormonal disturbances, chronic inflammation and endocrine dysfunction. It aims to increase clinical awareness and highlight the need for early diagnosis and intervention to mitigate the burden of osteosarcopenia on the quality of life and healthcare systems in ageing CKD populations. A narrative review of the current literature was conducted, summarising evidence on the mechanisms underlying osteosarcopenia in CKD, including mineral metabolism alterations, inflammatory processes and hormonal imbalances. Osteosarcopenia is a recognised consequence of CKD, contributing to increased morbidity and mortality. The pathophysiology of osteosarcopenia in CKD is multifactorial, involving disruptions in mineral metabolism, inflammation, endocrine dysfunction and physical inactivity. CKD-mineral and bone disorder (CKD-MBD) leads to alterations in calcium, phosphate, parathyroid hormone (PTH), fibroblast growth factor 23 (FGF-23) and vitamin D metabolism, resulting in impaired bone mineralisation and increased fracture risk. Simultaneously, CKD accelerates muscle wasting through systemic inflammation, anabolic resistance and metabolic derangements, increasing the risk of sarcopenia. Sarcopenic obesity, inflammaging and hormonal dysregulation further exacerbate bone muscle deterioration. Emerging evidence suggests that osteosarcopenia in CKD is a consequence of interconnected pathophysiological pathways rather than isolated conditions. Diagnosis remains challenging because of overlapping clinical features, necessitating integrated assessment tools. Targeted therapeutic strategies, including mineral metabolism correction, resistance exercise and anabolic interventions, are essential to mitigate osteosarcopenia's progression and improve patient outcomes in CKD. Osteosarcopenia is a growing concern in ageing CKD populations. Early diagnostic strategies and targeted interventions are essential to mitigate the impact of osteosarcopenia on patient outcomes and reduce associated healthcare costs. Increased clinical awareness and research into effective therapies are crucial for improving the quality of life for individuals affected by CKD and osteosarcopenia.

Role of Inflammatory Biomarkers in Mediating Causal Effect of Life Course Body Composition on Hypertension.

The mediating role of inflammatory biomarkers in the causal relationship between body composition and hypertension remains unclear and requires further investigation. This study used a combination of retrospective observational analysis and Mendelian randomization approaches. Observational data were derived from 4717 Chinese children and adolescents aged 6 to 18 years who underwent dual-energy X-ray absorptiometry to assess body composition. Mendelian randomization analyses utilized summary statistics from large-scale data sets, including UK Biobank, deCODE2021, International Consortium of Blood Pressure, FinnGen, and other consortia. The inflammatory biomarkers included leptin, insulin, adiponectin, osteocalcin, FGF23 (fibroblast growth factor 23), and PTH (parathyroid hormone). The observational analysis revealed that increased fat mass positively influenced diastolic blood pressure through osteocalcin, while fat-free mass had an inverse effect. Insulin mediated the association between fat mass and systolic blood pressure, diastolic blood pressure, and hypertension, with additional indirect effects observed for PTH (all P<0.05). The Mendelian randomization analyses demonstrated a causal relationship between childhood body mass index and hypertension mediated by insulin (indirect effect: odds ratio, 0.87 [95% CI, 0.78-0.97]) and adiponectin (odds ratio, 1.13 [95% CI, 1.04-1.23]). Adiponectin mediated the effects of fat-free mass (odds ratio, 0.81 [95% CI, 0.71-0.93]) and fat mass (odds ratio, 1.30 [95% CI, 1.11-1.51]) on hypertension. Leptin, adiponectin, and insulin also mediated the causal effects of body composition on systolic blood pressure, diastolic blood pressure, and hypertension. These findings indicate that body composition influences blood pressure through distinct inflammatory biomarkers. Targeting inflammatory biomarkers may provide tailored strategies for managing body composition and hypertension.

Association of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study.

In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and influences patient's outcome and prognosis. However, evaluation methods for VC severity are limited. Klotho and fibroblast growth factor-23 (FGF-23) are biomarkers associating with VC development. This study aimed to explore the association of serum Klotho and FGF-23 levels with VC severity in patients with non-dialysis CKD. Patients with non-dialysis CKD were enrolled during hospitalization and were divided into the following four groups on the basis of their coronary artery calcification (CAC) scores: non-VC (CAC scores = 0), mild VC (0 < CAC scores ≤ 100), moderate VC (100 < CAC scores ≤ 400), and severe VC groups (CAC scores > 400). Serum Klotho and FGF-23 levels among the different groups were compared. A total of 154 non-dialysis CKD patients were enrolled. Correlation analysis showed that serum FGF-23 level (rho = 0.185, p = 0.022) was positively correlated with VC severity, whereas serum Klotho level (rho = - 0.196, p = 0.015) was negatively correlated with VC severity in patients with CKD. Multivariable regression analysis showed that Klotho level [odd ratio (OR) = 0.998, 95% confidence interval (CI) 0.996-0.999, p = 0.001] served as a protective factor for VC severity in patients with CKD, whereas FGF-23 level (OR = 1.005, 95% CI 1.001-1.009, p = 0.020) was identified as risk factor for VC severity. Serum Klotho and FGF-23 levels are potential predictors of VC severity in patients with non-dialysis CKD.

Fibroblast growth factor 23 neutralizing antibody partially rescues bone loss and increases hematocrit in sickle cell disease mice

Fibroblast Growth Factor 23 (FGF23) is increased in serum of humanized Sickle Cell Disease (SCD) mice. Since FGF23 is associated with impaired bone formation, we examined the effect of FGF23-neutralizing antibody (FGF23Ab) on bone loss in SCD mice. Healthy control (Ctrl) and SCD 5-months-old female mice were treated with FGF23Ab or isotype-specific IgG for 6 weeks. Significantly reduced hematocrit in SCD mice was increased by FGF23Ab. MicroCT of SCD femurs revealed no significant reduction in metaphyseal bone volume/total volume vs. Ctrl mice. However, histomorphometry of SCD femur revealed significantly reduced mineral apposition rate, bone formation rate, inter-label thickness, and osteoid surface, which were increased by FGF23Ab. Significantly increased osteoclast number/bone perimeter in SCD mice was reduced by FGF23Ab. Bone marrow stromal cells (BMSC) cultured in osteogenic media revealed significantly reduced mineralized nodules in SCD-IgG-BMSC that was increased in SCD-FGF23Ab-BMSC. FGF23 and αKlotho protein was significantly increased in SCD-IgG-BMSC and was not reduced by FGF23Ab. However, phosphorylated FGF Receptor-1, the receptor through which FGF23 signals, was significantly reduced by FGF23Ab. The mineralization inhibitor osteopontin was significantly increased in SCD-IgG-BMSC cultures and was reduced by FGF23Ab. We conclude that FGF23Ab may be efficacious in improving some parameters of reduced bone formation in female SCD mice.

Comparison of Serum FGF23 Levels and CKD-MBD Parameters in Home Hemodialysis and Center Hemodialysis

Purpose:This study aims to compare serum fibroblast growth factor 23 (FGF23) levels and chronic kidney disease-mineral and bone disorder (CKD-MBD) parameters in patients undergoing home hemodialysis (HHD) and center hemodialysis (CHD). Materials and methods: A total of 42 patients over 18 years old who had been receiving dialysis treatment for at least six months were included in the study. The patients were divided into two groups: HHD (n=17) and CHD (n=25). Demographic data, dialysis duration, biochemical parameters (serum phosphorus, calcium, parathyroid hormone, albumin, hemoglobin, FGF23, etc.), and medication use were recorded. Serum FGF23 levels were measured using the ELISA method from blood samples taken before midweek HD sessions. Frequency distributions were expressed as percentages and compared using the chi-square test. Results: The Kt/V values were higher in the HHD group (2.4±0.1 vs. 1.6±0.1), while serum phosphorus levels were lower (4.1±1.1 vs. 5.0±1.2 mg/dL). Although FGF23 levels were lower in the HHD group, the difference was not statistically significant (383±423 vs. 441±480 pg/mL, p&gt;0.05). Erythropoietin (Epo) usage was significantly lower in the HHD group (47% vs. 92%, p=0.001). Conclusion: HHD was associated with better phosphorus control and a reduced requirement for EPO compared to CHD. The lower FGF23 levels in HHD suggest that this modality may offer advantages in CKD-MBD, cardiovascular outcomes, and mortality. However, these findings need to be supported by prospective studies involving larger patient populations.

Correlation linking fibroblast growth factor 23 in circulation (FGF-23) and serum aldosterone levels in different stages of chronic kidney disease

BackgroundChronic kidney disease (CKD) continues to pose a serious medical issue. To date, the detection of CKD relies on renal function estimate and radiology. Hence, new sensitive diagnostic and prognostic bioindicators are urgently needed for early diagnosis and surveillance of CKD. This study aimed to assess the correlation linking fibroblast growth factor 23 (FGF23) in circulation and serum aldosterone levels in cases with CKD of different stages and investigate the theory that aldosterone may directly cause elevated FGF23 secretion in these cases.MethodsOur observational cross-sectional research was performed on 140 patients divided into: group A: 70 cases with diverse stages of recently discovered CKD that had not yet begun treatment with renin–angiotensin–aldosterone system (RAAS) blockers (CKD stages 1–5) and group B: 70 normal control subjects.ResultsThe levels of serum aldosterone and circulating FGF-23 levels varied significantly among CKD cases. High levels of circulating FGF-23 and serum aldosterone each considerably raise the risk of CKD by 1.15 and 1.043 times, correspondingly. With a sensitivity of 91.4%, a specificity of 90%, a positive predictive value of 90.1%, a negative predictive value of 91.3%, and an overall accuracy of 90.7%. The optimal cutoff value for FGF-23 was a prediction of kidney damage at ≥ 59,735 (p < 0.001). Patients’ FGF-23 levels and their CKD stages showed a strong correlation. For renal damage prediction, the optimal cutoff value for aldosterone is ≥ 117.59, with an area under the curve of 0.978, a sensitivity of 92.9%, a specificity of 88.6%, a positive predictive value of 89%, a negative predictive value of 92.5%, and an overall accuracy of 90.7% (p < 0.001). Our study found that FGF-23, age, and estimated glomerular filtration rate (eGFR) were the sole factors strongly related to aldosterone in CKD patients.ConclusionThere was a significant correlation linking circulating FGF23 and serum aldosterone levels among CKD cases, suggesting their potential as independent predictors of CKD progression. Both circulating FGF23 and aldosterone levels were considerably elevated in CKD cases in comparison with normal controls, highlighting their predictive performance.

Effects of a high-fat diet on gut microbiota and possible implications for bone health in male Wistar rats.

Diet plays an important role in the composition of gut microbiota. Emerging research suggests that bone homeostasis can also be influenced by the gut microbiota. The aim of this study was to assess possible alterations in gut microbiota in an experimental obesity model induced by a high-fat diet (HFD) and the possible effects on parameters of bone metabolism and remodeling. Male Wistar rats were fed a HFD (60% lipids) or standard (control) diet for 14 weeks. Biochemical and hormonal parameters, bone histomorphometry, bone protein levels, and gut microbiota composition were analyzed. HFD animals exhibited a greater gut microbiota α-diversity represented by the Shannon Index and an increased relative abundance of the Proteobacteria phylum. Histomorphometry detected lower bone formation in the HFD group, accompanied by increased levels of serum and bone leptin and FGF-23 (fibroblast growth factor-23). The Shannon Index was correlated directly with bone FGF-23 (R 0.96, p = 0.04) and inversely with the osteoblastic surface (R -0.95, p = 0.04). The present study disclosed a significant increase in gut microbiota α-diversity and relative abundance of Proteobacteria phylum in obese animals fed a high-fat diet in parallel with increased levels of bone and serum leptin and FGF-23 and lower bone formation. The associations of Shannon Index with bone levels of FGF-23 and reduced osteoblastic surface suggest a link between HFD-induced higher gut microbiota diversity and low bone formation.

Maternal Inflammatory Proteins in Pregnancy and Neurodevelopmental Disorders at Age 10 Years

Maternal inflammation during pregnancy has been associated with an increased risk of neurodevelopmental disorders (NDDs), such as attention-deficit/hyperactivity disorder (ADHD) and autism, and cognitive deficits in early childhood. However, little is known about the contributions of a wider range of inflammatory proteins to this risk. To determine whether maternal inflammatory proteins during pregnancy are associated with the risk of NDDs and executive functions (EF) in middle childhood and to identify protein patterns associated with NDDs and EF. This was a 10-year follow-up cohort study of the Danish Copenhagen Prospective Studies on Asthma 2010 mother-child birth cohort, using plasma samples collected at week 24 in pregnancy, where 92 inflammatory proteins were assessed. NDDs and EF were assessed in the offspring at age 10 years, between January 2019 and December 2021. Mother-offspring dyads with available maternal prenatal inflammatory proteins during pregnancy and offspring NDD psychopathology data at follow-up were included. Data analyses took place between December 2023 and August 2024. Levels of 92 inflammatory proteins from panel collected at week 24 during pregnancy. Categorical and dimensional psychopathology of NDDs (primary outcome) and EF (secondary outcome). A total of 555 mothers (mean [SD] age, 32.4 [4.3] years) and their children (285 male [51%]) were included. The principal component analysis showed that higher levels of maternal inflammatory proteins depicted in principal component 1 were associated with a higher risk of any NDD (OR, 1.49; 95% CI, 1.15-1.94; P = .003), particularly autism (OR, 2.76; 95% CI, 1.45-5.63; P = .003) and ADHD with predominantly inattentive presentation (OR, 1.57; 95% CI, 1.05-2.39; P = .03). The single protein analysis showed that 18 of 92 proteins reached false discovery rate (FDR) 5% significance after adjustment. Vascular endothelial growth factor A, C-C motif chemokine ligand, CD5, interleukin 12B, fibroblast growth factor-23, and monocyte chemoattractant protein-1 emerged as top proteins associated with risk of NDDs. The sparse partial least squares approach identified 34 proteins associated with any NDD, and 39 with ADHD with predominantly inattentive presentation. There were no associations with EF after FDR correction. The maternal inflammatory proteome during pregnancy was associated with NDDs risks in offspring at age 10 years. Further research is warranted to elucidate the specific pathways involving these proteins during pregnancy that could be targeted with prevention strategies to reduce risk of NDDs in children.

Primary hyperparathyroidism induces erythropoietin resistance through fibroblast growth factor 23.

Primary hyperparathyroidism (PHPT) often causes hypercalcemia and complications requiring parathyroidectomy (PTX). Anemia affects 15%-50% of PHPT patients, but its mechanisms remain unclear. While parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) contribute to anemia in secondary hyperparathyroidism through erythropoietin (EPO) resistance and bone marrow fibrosis, their roles in PHPT are less defined. This study explores the effect of PHPT on erythropoiesis by assessing hemoglobin (Hb), EPO, and FGF23 levels before and after PTX. In a monocentric longitudinal study (2018-2020), PHPT patients scheduled for PTX were followed for 6 months. Blood and urine samples were collected at baseline (surgery day), at 10 days and 6 months postsurgery. Pearson correlation assessed relationships between Hb, EPO, PTH, FGF23, calcium, and phosphate at baseline and 6 months. Mixed-effects models evaluated the impact of PTH and FGF23 on Hb, adjusting for confounders. In a cohort of 111 PHPT patients (81% women, median age 64, normal body mass index), anemia prevalence decreased from 9.9% at baseline to 2.7% 6 months post-PTX, despite stable EPO levels. Postsurgery, PTH, FGF23, and calcium significantly decreased. PTH did not significantly correlate with Hb or EPO at any time point. Before surgery, FGF23 negatively correlated with Hb (R = -0.20, P = .020) and positively correlated with log-EPO (R = 0.38, P < .001). Mixed-effects models showed no predictive effect of PTH on Hb. However, multivariable models indicated a significant association between FGF23 and declining Hb (β = -.01, 95% confidence interval [-0.02; -0.01]). Anemia in PHPT is linked to elevated FGF23 levels, potentially causing EPO resistance.

FGF-23 as a Biomarker for Carotid Plaque Vulnerability: A Systematic Review.

Carotid artery disease is a condition affecting 3% of the general population which significantly contributes to the development of cerebrovascular events. Fibroblast Growth Factor-23 (FGF-23) is a hormone that has been linked to atherosclerosis and increased cardiovascular risk, including stroke and myocardial infarction. This review explores the association of FGF-23 with carotid artery disease progression in an endarterectomy clinical context. Based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), a search was performed relying on MEDLINE, Scopus and Web of Science, identifying publications focused on the correlation between serum FGF-23 and carotid artery disease. Assessment of study quality was made using National Heart, Lung and Blood Institute Study Quality Assessment Tool (NHLBI). Three observational studies, comprising 1039 participants, were included. There was considerable heterogeneity among the populations from the different studies. Elevated FGF-23 levels were consistently associated with unstable plaque features, including intraplaque neovascularization, as identified through Superb Microvascular Imaging (SMI). Plasma levels of inflammatory mediators, such as Interleukin-6 (Il-6), Monocyte Chemoattractant Protein-1 (MCP-1), and Osteoprotegerin (OPG), positively correlated with carotid artery disease, but their link to unstable plaques is conflicting. None of the studies investigated clinical complications following carotid endarterectomy. FGF-23 is a potential biomarker for plaque vulnerability in carotid disease. Despite promising findings, limitations such as small sample sizes and lack of longitudinal data suggest the need for larger and more diverse studies to improve risk stratification and inform personalized treatment strategies for carotid atherosclerosis.

Real-world efficacy and safety of Burosumab in tumor-induced Osteomalacia: case series from an early access program

Abstract Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome due to a phosphaturic tumor, which overproduces Fibroblast Growth Factor 23 (FGF23), causing hyperphosphaturia, hypophosphatemia, low 1,25(OH)2D and osteomalacia. Complete surgical resection is the standard of care, but some tumors cannot be found, and others cannot be removed. In such difficult situations, burosumab, a fully human monoclonal antibody that targets and inhibits excess circulating FGF23, is a treatment option. Early access program (EAP) to burosumab has been established for patients with TIO in France in July 2022. Before that, access to burosumab at no cost on compassionate grounds was provided for a few patients. Between July 21, 2022, and December 3, 2023, an EAP was initiated for burosumab across ten University Hospital Centers. The program included nine patients (3 pre-exposed and 6 burosumab-naïve patients). The EAP included assessments of phosphatemia, pain levels using the Visual Analogue Scale (VAS), and quality of life using the RAPID-3 (Routine Assessment of Patient Index Data 3) questionnaire. Patients’ ages ranged from 33 to 62 years, with various BMI categories. Seven patients had at least one follow-up visit (3 pre-exposed and 4 burosumab-naïve patients). In the burosumab-naïve group, phosphatemia levels improved in two patients, with one achieving levels &amp;gt;0.8 mmol/L. Pain reduction was reported in all four naïve patients with follow-up, while pain levels in pre-exposed patients remained stable or fluctuated. Quality of life scores indicated minimal impairment or remission in six patients at baseline. No serious adverse events were observed. These preliminary findings following burosumab EAP for patients with TIO in France support benefits in terms of efficacy, safety, and ease of treatment. Burosumab appears to be a promising option for patients who are ineligible or refractory to surgery.

Two Cases of Tumor-induced Osteomalacia Resulting in Surgical Resection During Burosumab Therapy.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome that results from tumors that secrete fibroblast growth factor 23 (FGF23). This leads to chronic hypophosphatemia. Burosumab, an anti-FGF23 antibody, is an effective treatment when surgery is not possible; however, it complicates FGF23 measurements and postoperative monitoring. We describe the first case report of TIO in which the responsible tumors were discovered during burosumab therapy and successfully resected. Despite tumor removal, the serum FGF23 levels remained elevated. In the postoperative monitoring of patients treated with burosumab, physicians should focus on the serum and urine levels of phosphate rather than FGF23.

Connecting Bone Remodeling and Regeneration: Unraveling Hormones and Signaling Pathways.

Recent advancements in tissue engineering and stem cell science have positioned bone disease treatment as a promising frontier in regenerative medicine. This review explores the hormonal and signaling pathways critical to bone regeneration, with a focus on their clinical relevance. Key endocrine factors, including thyroid hormones (T3 and T4), insulin-like growth factor 1 (IGF-1), bone morphogenetic proteins (BMPs), parathyroid hormone (PTH), calcitonin, and fibroblast growth factor 23 (FGF23), play pivotal roles in bone remodeling by regulating osteoblast activity, bone resorption, and mineralization. These factors primarily act through the Wnt/β-catenin, BMP, and FGF signaling pathways, which govern bone repair and regeneration. While animal models, such as axolotls, zebrafish, and Xenopus laevis, provide valuable findings about these mechanisms, translating these findings into human applications presents challenges. This review underscores the therapeutic potential of modulating these hormonal networks to enhance bone regeneration while cautioning against possible adverse effects, such as uncontrolled tissue proliferation or metabolic imbalances. By integrating knowledge from regenerative models, this work provides a foundation for optimizing hormone-based therapies for clinical applications in bone repair and disease treatment.