The AMPK/ULK1/autophagy pathway: FGF23's weapon against GSDME-mediated pyroptosis in folic acid-induced acute kidney injury.

Osteosarcoma is a highly malignant bone tumor affecting children and adolescents. Once metastasis occurs, the five-year survival rate drops to ~20%, emphasizing the need for new therapies. Fibroblast growth factor-23 (FGF-23), a bone-derived hormone, has been implicated in tumor progression, but its role in osteosarcoma remains unclear. Bioinformatics analysis using the R2 database revealed that elevated FGF-23 expression is associated with increased metastasis and reduced overall survival in osteosarcoma patients. Functional assays confirmed that FGF-23 enhances the migratory ability of osteosarcoma cells. Gene Expression Omnibus (GEO) analysis indicated that lysyl oxidase-like proteins-particularly LOXL1, LOXL2, and LOXL3-are overexpressed in osteosarcoma tissues compared to adjacent normal bone. In vitro experiments further showed that FGF-23 significantly upregulates LOXL2 expression in 143B and MG63 osteosarcoma cells, while LOXL2 knockdown via small interfering RNA (siRNA) markedly reduces cell migration. Moreover, pretreatment with ERK, p38, and JNK inhibitors or siRNAs targeting these pathways suppressed both FGF-23-induced LOXL2 expression and wound healing, indicating that FGF-23 promotes cell motility through ERK-, p38-, and JNK-dependent LOXL2 upregulation. FGF-23 stimulation also increased phosphorylation of ERK, p38, and JNK, and downregulated miR-4463. Inhibition of these pathways restored miR-4463 levels and suppressed LOXL2 expression. Taken together, these findings suggest that FGF-23 promotes osteosarcoma cell migration and may contribute to metastasis through coordinated regulation of the miR-4463/LOXL2 axis via ERK, p38, and JNK signaling. Targeting FGF-23 or its downstream signaling cascades may offer a promising therapeutic approach for metastatic osteosarcoma.

Pyrophosphate dysregulation and impaired FGF23/FGFR signaling contributes to impaired matrix mineralization in bone marrow stromal cultures from sickle cell disease mice.

Subchronic co-exposure to dibutyl phthalate and benzo(a)pyrene exacerbates renal inflammation and fibrosis in rat: Crosstalk between tubular epithelial cells and fibroblasts.

Introduction Diabetic kidney disease (DKD) is a common and serious complication in patients with diabetes mellitus (DM). This study was aimed to reveal the validity of seven emerging novel biomarkers of angiopoietin-like-4 (ANGPTL4), neutrophil gelatinase-associated lipocalin (NGAL), monocyte chemoattractant protein-1 (MCP-1), growth differentiation factor-15 (GDF15), fibroblast growth factor-23 (FGF23), n-terminal osteopontin (ntOPN) and pyruvate kinase muscle isozyme M2 (PKM2) in detecting DM patients at high risk of DKD and establish prediction models for DKD onset in DM patients. Methods This was a cross-sectional study of 348 adult patients with Type 1 DM for at least 5 years, or Type 2 DM, followed by a prospective observational cohort of 141 adult DM patients without renal involvement at baseline and follow-up for at least 2 years. We performed logistic regression analysis to analyze the relationship between the variables and the risk of DKD occurrence, and receiver operator characteristic (ROC) analysis to assess the predictive ability of multi-biomarker panels for DKD onset. Results In the cross-sectional cohort, the seven urinary biomarkers were all elevated in DKD patients, of which the high levels of urinary ntOPN, GDF15, NGAL, MCP-1 and FGF23 significantly increased the risk of DKD diagnosis; the urinary MCP-1 alone performed best in DKD detection with the largest area under the ROC curve (AUC). In the prospective cohort, the high levels of urinary GDF15, MCP-1, ANGPTL4 and FGF23 significantly increased the risk of DKD development, and the model constructed based on the above four biomarkers had the largest AUC (0.873) for predicting the 2-year risk of DKD occurrence. Conclusion Our study demonstrated that the four-biomarker model performed the best in predicting DKD, which could provide more accurate tools for DKD risk prediction, thereby improving the prognosis in DM patients.

Schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) share common genetic and environmental risk factors, with immune-inflammatory dysregulation playing a crucial role in their pathophysiology. However, further research is needed to clarify causal relationships. We conducted a Mendelian randomization (MR) study using summary statistics from large-scale genome-wide association studies (GWAS) of European ancestry as instrumental variables to assess the association between 95 circulating inflammatory proteins and the risk of SCZ, BD, and MDD. Initially, a bidirectional two-sample MR analysis was performed to clarify the direction of causality. Subsequently, multivariable MR analysis was employed to investigate whether the effects of different circulating proteins on psychiatric disorders exhibit complex overlap or interrelated effects. Finally, colocalization analysis was applied to determine whether circulating proteins share causal genetic variants with psychiatric disorders. To enhance the robustness of our findings, a series of sensitivity analyses were conducted, including tests for horizontal pleiotropy, heterogeneity, and rigorous quality control procedures. Discovery analyses were based on data from the Psychiatric Genomics Consortium (PGC), while validation was performed using data from the FinnGen biobank. Meta-analysis was used to integrate results from multiple data sources. Evidence strength was evaluated based on consistency across MR, replication, and colocalization. Forward univariable MR and meta-analysis revealed that elevated circulating C-reative protein (CRP) (OR = 0.93, Pmeta = 0.013) and fractalkine(CX3CL1) (OR = 0.92, PIVW = 0.040) significantly reduced the risk of SCZ, whereas Delta and Notch-like epidermal growth factor-related receptor (DNER) (OR = 1.07, Pmeta = 0.007) and eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1)(OR = 1.09, PIVW = 0.015) was associated with an increased risk of SCZ. For MDD, fibroblast growth factor 23 (FGF23) (OR = 0.97, Pmeta = 0.015) and interleukin-20 (IL20) (OR = 0.96, PIVW = 0.028) significantly reduced the risk, whereas tumor necrosis factor ligand superfamily member 12 (TNFSF12) was associated with an increased risk of MDD (OR = 1.02, Pmeta = 0.039). In BD, elevated circulating levels of C-X-C motif chemokine 5 (CXCL5) (OR = 0.95, PIVW = 0.024), TRANCE (OR = 0.95, Pmeta = 0.016), and CC motif chemokine ligand 7 (CCL7) (OR = 0.94, Pmeta = 0.023) were significantly associated with reduced risk, suggesting potential protective effects. In multivariable MR analysis, after adjusting for other inflammatory protein levels, CRP showed a significant protective effect on SCZ (OR = 0.91, PIVW = 0.008), FGF23 demonstrated a significant protective effect on MDD (OR = 0.96, PIVW = 0.038), and TNFSF12 significantly increased the risk of MDD (OR = 1.03, PIVW = 0.032). Colocalization analysis provided strong evidence for shared genetic variants between DNER and SCZ (PH4 = 0.89), with the rs35975053 locus being the most significant. This MR study suggests potential causal links between inflammatory proteins and psychiatric disorders. CRP and CX3CL1 were protective for SCZ, while DNER and EIF4EBP1 increased risk. FGF23 and IL20 were protective for MDD, whereas TNFSF12 increased risk. CXCL5, TRANCE, and CCL7 were suggestively protective for BD. The shared causal genetic variants between DNER and SCZ suggest a mechanism underlying neuropsychiatric pathogenesis. Further experimental studies are warranted to elucidate the underlying biological mechanisms and identify novel diagnostic biomarkers and therapeutic targets.

Patients with nephrotic syndrome develop albuminuria, hyperlipidemia and heart failure, but the pathomechanisms underlying this interconnection are unclear. We previously found that fibroblast growth factor 23 (FGF23) promotes cardiac hypertrophy in animal models of chronic kidney disease (CKD). Since patients with nephrotic syndrome have elevated FGF23, we hypothesized that FGF23 also contributes to heart damage in nephrotic syndrome. We previously developed a mouse model with the inducible and podocyte-specific overexpression of a constitutively active NFATc1 mutant variant (NFATc1nuc), which within one week develops a nephrotic syndrome-like phenotype. Here we conducted serological analyses of phosphate and lipid metabolism, and we studied the cardiac phenotype after one week and three months of albuminuria. After one week, mice presented with albuminuria, hyperlipidemia and elevated serum FGF23 levels, as well as reductions in cardiac function and cardiac hypertrophy on a cellular level without significant increases in cardiac mass or fibrosis. Under physiologic conditions and in CKD, elevations in systemic phosphate levels, also called hyperphosphatemia, induce FGF23 production in the bone. However, in NFATc1nuc mice we could detect neither increases in serum phosphate levels nor in FGF23 expression in the bone. Instead, nephrotic mice had FGF23 elevations in the heart, and our in vitro studies showed that free fatty acids induced FGF23 expression in cardiac myocytes resulting in hypertrophy. We also found that mice with prolonged NFATc1nuc expression transition into a CKD-like phenotype with hyperphosphatemia and further FGF23 elevations, as well as cardiac hypertrophy and fibrosis and a reduced lifespan. Our study suggests that NFATc1nuc mice serve as a model of nephrotic syndrome that progresses to CKD with pathologic cardiac remodeling. Our findings indicate that hyperlipidemia might contribute to heart failure in nephrotic syndrome by inducing FGF23 expression in the heart, which then drives cardiac hypertrophy.

Myocardial infarction (MI) and heart failure (HF) are associated with low bone mineral density (BMD). We aimed to investigate whether MI and HF directly cause bone loss using three different experimental models of cardiac injury. Firstly, terminal myocardial infarction was induced in adult wild-type mice by coronary ligation, followed by peripheral quantitative computed tomography (pQCT) and histomorphometric and biochemical analyses at 4 and 9 weeks post-infarction. Secondly, myocardial ischemia–reperfusion injury (I/R) was performed in 4- and 9-month-old rats, followed by bone phenotyping 4 weeks after injury. Finally, transverse aortic constriction (TAC) was performed in adult wild-type mice, double Fgf23/VDR (fibroblast growth factor-23/vitamin D receptor) mutants, and VDR-deficient mice to investigate bone changes in an HF model caused by afterload-induced cardiac hypertrophy, 4 and 6 weeks after TAC. We found unchanged BMD after MI, in both the terminal ischemia model in mice and in the myocardial I/R injury model in young and aged rats. On the other hand, TAC significantly reduced especially cortical BMD in femora. Global knockout of Fgf23 in Fgf23/VDR compound mutants did not rescue the TAC-induced skeletal phenotype. Collectively, our data demonstrate that TAC-induced HF, but not MI, is causing bone loss in mice in an FGF23-independent manner.

Introduction: Fibroblast growth factor 23 (FGF23) levels are markedly elevated in patients with kidney failure, but the mechanisms are incompletely understood. Recent evidence suggests that kidney-derived glycerol-3-phosphate (G-3-P), a glycolytic byproduct, mediates FGF23 production in response to dietary phosphate loading. However, the role of G-3-P is unknown in patients with kidney failure. Methods: Serum G-3-P levels were quantified by LC/MS in 35 healthy individuals and 650 patients undergoing hemodialysis. Association between serum phosphorus and G-3-P was examined using unadjusted and multivariable linear regression models. We next analyzed the associations of G-3-P and known regulators of FGF23 production with serum FGF23. Results: Median serum G-3-P level in patients undergoing hemodialysis was 220 ng/mL (IQR, 118-325), 2.2-fold higher than that of healthy individuals (98 ng/mL; IQR, 80-129). In patients undergoing hemodialysis, higher serum phosphorus was strongly associated with increased G-3-P in the unadjusted model; this association persisted after multivariate adjustment and when restricted to patients undergoing hemodialysis for over 10 years. In univariate analyses, higher serum phosphorus, calcium, intact PTH, and G-3-P, and active vitamin D use were each significantly associated with higher FGF23. Multivariate analysis identified G-3-P as an independent predictor of FGF23. Further adjustment for transferrin saturation, ferritin, and C-reactive protein did not change these findings. Conclusion: Even in patients with kidney failure, G-3-P may rise in response to phosphate retention and act as a regulator of FGF23 production. Further studies are needed to test these hypotheses and determine whether the apparently non-functioning kidney retains the capacity to produce G-3-P.

ABSTRACTTertiary lymphoid structures (TLS) are associated with inflammatory kidney diseases, but their pathogenesis is unclear. A chronic high phosphate diet (HPD) in mice increases serum levels of phosphate and fibroblast growth factor 23 (FGF23) which is associated with progressive tubule damage and fibrosis. We hypothesized that chronic HPD induces TLS in the kidneys and thereby promotes progressive kidney injury. After only 2 months, mice on HPD showed increased tubule damage accompanied by the formation of perivascular immune cell clusters of B and T cells in the corticomedullary zone and in the cortex. In addition, lymphatic vessels were observed, accompanied by increased expression of venous markers and cell adhesion molecules. Further analyses showed a time‐dependent induction of the immunofibroblast‐derived chemokines and lymphotoxins, which are important for the differentiation of immunofibroblasts into follicular dendritic cells (FDC) and fibroblastic reticular cells (FRC). Already after 4 months of HPD, proliferating B‐cell clusters with FDCs, T‐cell clusters with FRCs, podoplanin+ cellular networks, high endothelial venules, plasma cells and increased IgD synthesis indicated fully mature TLSs, while tubular damage and fibrosis continued to increase up to 6 months of feeding HPD. Genetically modified mice overexpressing FGF23 developed tubular damage, fibrosis, and fully mature TLS only in the presence of HPD‐induced hyperphosphatemia. Likewise, hypophosphatemic Hyp mice showed no signs of tubular damage or TLS despite increased FGF23 levels. Our data suggest that high phosphate directly causes chronic inflammation in the kidney leading to the development of fully mature TLS associated with progressive tubular injury.

In-stent restenosis (ISR) after vertebral artery stenting (VAS) affects 20-35% of patients, yet current risk stratification lacks sensitivity for early intervention. We propose the first combined biomarker model integrating endothelin-1 (ET-1) and fibroblast growth factor 23 (FGF23) to address this gap. A prospective cohort study was conducted involving 148 patients who underwent VAS between 2020 and 2024. Blood samples were collected preoperatively to measure ET-1 and FGF23 levels. ISR was defined as a stenosis of at least 50% on follow-up imaging. Statistical analyses included multivariable logistic regression and receiver operating characteristic (ROC) curve evaluations to assess the biomarkers' performance. ISR occurred in 34 patients (23%). Both ET-1 and FGF23 levels were significantly higher in the ISR group. Multivariate analysis identified ET-1, FGF23, stent length, and LDL-C levels as independent predictors of ISR. The combined model using both biomarkers demonstrated superior discriminative performance (AUC = 0.96) compared to individual markers (AUC = 0.73 for ET-1 and AUC = 0.77 for FGF23). The model achieved sensitivity and specificity of 92.3% and 89.7%, respectively. The combined assessment of serum ET-1 and FGF23 exhibits a synergistic predictive role for ISR after VAS. The ET-1/FGF23 model enables personalized risk stratification, guiding targeted therapies to reduce recurrent ischemic events and healthcare costs.

X-linked hypophosphatemia (XLH) is an X-linked dominant condition where fibroblast growth factor-23 (FGF23) excess leads to hypophosphatemic rickets, lower limb bowing, and musculoskeletal pain. Burosumab, a monoclonal antibody against FGF23, has been shown to ameliorate the clinical phenotype of XLH and has recently been approved for use in many countries. This study aimed to evaluate patient and parental/caregiver perception of burosumab therapy and the acceptability of current management practices in Australia. Children with XLH and parents/carers were invited to respond to a survey on clinical and management information including use of telehealth, access to multidisciplinary team members, and perceptions and experience regarding burosumab therapy. This was a multi-centre, cross-sectional survey-based study involving 4 tertiary Australian children’s hospitals. A total of 21 survey responses from parents/carers were received between December 2022 and October 2023. Mean (SD) age at time of survey was 12.7 (4.1) yr and median time on burosumab was 42 mo (range 2-100). Reported side effects of burosumab were limited to local skin reactions (38%, n = 8) and injection site pain (5%, n = 1), with the majority (62%, n = 13) reporting no side effects. Logistical issues (availability from the pharmacy or medical centre holiday closure) led to most instances of missed or delayed doses, which were reported by 24% (n = 5). Most participants reported seeing their specialist both face-to-face and via telehealth (64%, n = 14). The majority saw an endocrinologist (100%, n = 21) and orthopaedic surgeon (67%, n = 14), but only a small minority saw a psychologist (10%, n = 2). Answers to Likert scale questions revealed that most parents/carers and children reported a perceived improvement in physical and psychological symptoms and function with burosumab therapy. This study supports the use of recently published local guidelines to manage children with XLH on burosumab due to high satisfaction expressed by children and parents/carers. However, logistical issues leading to delayed or missed doses should be addressed.

The incidence of osteoporosis is increased in Alzheimer's disease (AD). The pathogenesis of AD with osteoporosis is still unknown, there is no ideal treatment as yet for it. 7,8-Dihydroxyflavone (7,8-DHF), a functional brain-derived neurotrophic factor (BDNF) mimetic, shows therapeutic potential for neurological and orthopedic disorders. This research investigated the molecular mechanisms by which 7,8-DHF mitigates bone loss and cognitive dysfunction in osteoporotic AD mice. Micro-CT analysis quantified bone loss in AD mice. The Morris water maze (MWM) assessed mouse cognitive function, and immunohistochemical analysis measured Aβ plaque deposition. qPCR and Western blotting measured expression levels of APP, Aβ42, TRKB, and FOXO3a in osteoblasts isolated from femoral bone marrow mesenchymal stem cells (BMSCs) and brain tissue. ELISA determined the levels of IL-1β, IL-6, osteocalcin (OCN), fibroblast growth factor 23 (FGF23) and sclerostin. For in vitro experiments, osteoblast differentiation was monitored in MC3T3-E1 cells co-cultured with Aβ42, with concurrent measurement of TRKB, AKT, and FOXO3a expression. The efficacy of 7,8-DHF against bone loss and osteoblast differentiation was systematically evaluated. Cognitive impairment and bone loss manifested in APP/PS1 mice. 7,8-DHF treatment ameliorated bone mass reduction, decreased Aβ42 expression in bone tissue, and enhanced TRKB expression. Concurrently, 7,8-DHF improved cognitive function and accelerated clearance of [¹²⁵I]-Aβ42 from the brain. In in-vitro, Aβ42 increased inflammatory cytokine levels, suppressed TRKB expression, and impaired osteoblast differentiation. 7,8-DHF reduced the levels of AKT and pFOXO3a by TRKB. 7,8-DHF could alleviate bone mass loss in AD mice by regulating the TRKB/AKT/FOXO3a pathway. This finding provides new ideas for the treatment strategy of AD with osteoporosis and is beneficial to the health of the elderly.

Intravenous iron infusions (particularly ferric carboxymaltose) are associated with hypophosphatemia. This is mediated by increased fibroblast growth factor 23 (FGF-23), resulting in decreased activation of 25(OH)vitamin D to 1,25(OH)2 vitamin D and increased urinary phosphate excretion. Similarly, parenteral antiresorptive agents can lead to hypocalcemia due to reduced bone calcium mobilization, increasing parathyroid hormone (PTH) secretion, and exacerbating kidney phosphate excretion. When given concurrently, electrolyte disturbances can be severe and refractory to treatment, necessitating intravenous replacement, frequent monitoring, and prolonged hospitalization. We describe a case series of six patients with severe hypophosphatemia and hypocalcemia from concurrent administration of intravenous iron and antiresorptive therapy. The average time to hypophosphatemia following iron therapy in the presence of antiresorptives was 17.5 days. This is consistent with the nadir of phosphate 2 weeks following iron infusion and appears to be prolonged and exacerbated by antiresorptive therapy, increasing urinary phosphate loss through increased PTH activity. With the increasing popularity of intravenous iron infusions and parenteral antiresorptive agents, the interplay of these medications is an important consideration for clinicians. The emerging administration of these agents in the community and fragmentation of care across primary and specialist networks create the risk of unintentional concurrent use. Increased awareness of their impact on calcium-phosphate homeostasis is needed to mitigate the risk of severe electrolyte derangements with consideration of alternate iron formulations preferentially in those receiving medications for osteoporosis.

We report an atypical case of fibroblast growth factor-23 (FGF23)-mediated hypophosphatemic osteomalacia without a pathogenic variant (PV) of PHEX, who improved biochemically, clinically and radiologically post burosumab treatment. We present a narrative review of FGF23-mediated hypophosphatemic osteomalacia and propose a roadmap for investigating the etiology of hypophosphatemia to guide therapy. A 29-yr-old female with FGF23-mediated hypophosphatemic osteomalacia experienced multiple insufficiency fractures, including bilateral femoral diaphyseal fractures and delayed healing. This occurred on a background of juvenile enthesitis-related arthritis, narcolepsy, and brittle dentition since her early teens. Whole-body magnetic resonance imaging and gallium-68 DOTATATE PET scans were unremarkable, making tumor-induced osteomalacia highly unlikely. No hypophosphatemic PVs were found using massively parallel sequencing. Despite phosphate and calcitriol therapy, mild hypophosphatemia persisted with minimal improvement in fracture healing or pain. One dose of 60 mg burosumab, an anti-FGF23 antibody, led to hyperphosphatemia requiring dose titration and 3 doses of burosumab normalized renal tubular maximum reabsorption rate of phosphate relative to glomerular filtration rate. Burosumab led to fracture healing with callus formation corresponding with improved pain at fracture sites. Hypophosphatemic osteomalacia manifests with varus deformity of the lower limbs, gait disturbance, muscle weakness, enthesopathy, and dental necrosis. Evaluation of the etiology is crucial and requires an algorithmic approach to determine whether hypophosphatemia is renally-mediated, FGF23-mediated, acquired or inherited. The most common inherited cause of FGF23-mediated hypophosphatemic osteomalacia is X-linked hypophosphatemia (XLH) secondary to a PV of the PHEX gene. However, the absence of a PHEX PVs does not exclude a diagnosis of hereditary FGF23-mediated hypophosphatemic osteomalacia. Other inherited causes of this disorder include autosomal dominant and autosomal recessive hypophosphatemic rickets, fibrous dysplasia-McCune-Albright syndrome, cutaneous skeletal hypophosphatemia syndrome and osteoglophonic dysplasia. Burosumab significantly improves serum phosphate and fracture healing in XLH and may effectively treat other forms of FGF23-mediated hypophosphatemia.

Immunofluorescent characterization of Klotho and FGF23 in clear cell renal cell carcinoma: A pilot study.

Evaluation of serum FGF23 and serum magnesium levels in dogs and cats with acute kidney injury.

Integrating single-cell and bulk transcriptome analysis of fibroblast growth factor 23 (FGF23)-producing mesenchymal tumors reveals molecular basis of its secretory phenotype.

Advancing Patient Evidence in XLH (APEX): Baseline analysis of a global data unification program.

Type 2 diabetes (T2D) is associated with normal or higher bone mineral density (BMD), but there is a higher fracture rate. Hypoglycaemia does not affect BMD but may cause fractures directly through falls and may affect bone cellular metabolism. We examined circulating bone marker proteins (BMPs) in response to induced hypoglycaemia in T2D versus controls. A prospective exploratory parallel study design was conducted in T2D patients (n = 23) and healthy controls (n = 23) who underwent blood SOMAscan proteomic analysis of bone biomarkers at baseline, hypoglycaemia, and post-hypoglycaemia time points. Unadjusted repeated measures linear mixed modeling was used for analysis. Linear mixed modeling of the proteins showed that the way most BMPs changed over time did not differ between groups. At baseline, Dickkopf-related protein 1 (DKK1), cathepsin A, cathepsin S, and cathepsin Z were increased in T2D versus controls (p < 0.05), whilst fibroblast growth factor 23 (FGF23) was lower in T2D versus controls (p ≤ 0.05). Following hypoglycemia, transient changes from baseline occurred in DKK1, cathepsin A, cathepsin G, cathepsin H, cathepsin S, cathepsin Z, parathyroid hormone (PTH), Sphingosine kinase 1 and 2 (SPK1/2), and interleukin-1 beta (IL1 beta) over the post-hypoglycaemia time course. There was decreased cathepsin S in T2D from baseline to 24 h compared to the control group, and increased cathepsin Z at 24 h for both groups overall compared to baseline (p < 0.05). Baseline-raised cathepsins (A, S, Z) in T2D may enhance osteoclastic resorption, whilst raised DKK1 could inhibit osteoblast differentiation and suppress bone formation. Hypothetically, this may lead to a decline in bone quality through a resorption-enhanced, low bone formation imbalance. The effects of hypoglycaemia on bone physiology appear to extend significantly beyond the initial insult, as seen for cathepsin S and Z, which differed at 24 h compared to baseline.