Molecular Interaction of Soluble Klotho with FGF23 in the Pathobiology of Aortic Valve Lesions Induced by Chronic Kidney Disease.

Chronic kidney disease (CKD) is linked to greater prevalence and rapid progression of calcific aortic valve disease (CAVD) characterized by valvular leaflet fibrosis and calcification. Fibroblast growth factor 23 (FGF23) level is elevated, and anti-aging protein Klotho is reduced in CKD patients. However, the roles of FGF23 and Klotho in the mechanism of aortic valve fibrosis and calcification remain unclear. We hypothesized that FGF23 mediates CKD-induced CAVD by enhancing aortic valve interstitial cell (AVIC) fibrosis and calcification, while soluble Klotho inhibits FGF23 effect. Methods and Results: In an old mouse model of CKD, kidney damages were accompanied by aortic valve thickening and calcification. FGF23 levels in plasma and aortic valve were increased, while Klotho levels were decreased. Recombinant FGF23 elevated the inflammatory, fibrogenic, and osteogenic activities in AVICs. Neutralizing antibody or shRNA targeting FGF23 suppressed the pathobiological activities in AVICs from valves affected by CAVD. FGF23 exerts its effects on AVICs via FGF receptor (FGFR)/Yes-associated protein (YAP) signaling, and inhibition of FGFR/YAP reduced FGF23's potency in AVICs. Recombinant Klotho downregulated the pathobiological activities in AVICs exposed to FGF23. Incubation of FGF23 with Klotho formed complexes and decreased FGF23's potency. Further, treatment of CKD mice with recombinant Klotho attenuated aortic valve lesions. Conclusion: This study demonstrates that CKD induces FGF23 accumulation, Klotho insufficiency and aortic valve lesions in old mice. FGF23 upregulates the inflammatory, fibrogenic and osteogenic activities in AVICs via the FGFR/YAP signaling pathway. Soluble Klotho suppresses FGF23 effect through molecular interaction and is capable of mitigating CKD-induced CAVD.

Evaluation of maternal serum fibroblast growth factor-23 levels in fetal growth restriction and gestational hypertensive disease.

OBJECTIVE: The objective of this study was to determine serum fibroblast growth factor-23 levels in preeclampsia, eclampsia, gestational hypertension, and the presence of fetal growth restriction subgroups. METHODS: A total of 55 pregnant women with planned cesarean section were included in this cross-sectional study. They were divided into two groups, namely, control (25) and gestational hypertensive disease (30). The gestational hypertensive disease group was evaluated by dividing it into three subgroups (preeclampsia, eclampsia, and gestational hypertension) according to the clinical and laboratory findings of the disease and two subgroups (presence of fetal growth restriction and absence of fetal growth restriction) according to the birth weight percentile. Demographic parameters, obstetric history, physical examination findings, and laboratory values were evaluated. RESULTS: Demographic parameters and obstetric history were similar between the two groups, while gestational week of delivery was lower in the gestational hypertensive disease group (p=0.002). Laboratory parameters and serum fibroblast growth factor-23 (pg/mL) values were similar between the two groups. In the subgroup analysis for gestational hypertension, preeclampsia, and eclampsia, there was no statistically significant difference in serum fibroblast growth factor-23 levels between gestational hypertension, preeclampsia, eclampsia, and control groups. In the subgroup analysis based on the presence of fetal growth restriction, serum fibroblast growth factor-23 levels were similar to the control group in the gestational hypertensive disease absence of fetal growth restriction, while serum fibroblast growth factor-23 levels and serum calcium levels were statistically significantly lower in the gestational hypertensive disease with the presence of fetal growth restriction (p=0.044 and p<0.001, respectively). CONCLUSION: Serum fibroblast growth factor-23 levels are similar between pregnancies complicated with gestational hypertensive disease and normotensive pregnancies. However, serum fibroblast growth factor-23 levels were found to be lower in pregnancies complicated with gestational hypertensive disease with the presence of fetal growth restriction.

Fibroblast growth factor 23 inhibition attenuates steroid-induced osteonecrosis of the femoral head through pyroptosis.

Steroid-induced osteonecrosis of the femoral head (SONFH) is the predominant cause of non-traumatic osteonecrosis of the femoral head (ONFH). Impaired blood supply and reduced osteogenic activity of the femoral head are the key pathogenic mechanisms of SONFH. Fibroblast growth factor 23 (FGF23) levels are not only a biomarker for early vascular lesions caused by abnormal mineral metabolism, but can also act directly on the peripheral vascular system, leading to vascular pathology. The aim of this study was to observe the role of FGF23 on bone microarchitecture and vascular endothelium, and to investigate activation of pyroptosis in SONFH. Lipopolysaccharide (LPS) combined with methylprednisolone (MPS) was applied for SONFH mouse models, and adenovirus was used to increase or decrease the level of FGF23. Micro-CT and histopathological staining were used to observe the structure of the femoral head, and immunohistochemical staining was used to observe the vascular density. The cells were further cultured in vitro and placed in a hypoxic environment for 12 h to simulate the microenvironment of vascular injury during SONFH. The effect of FGF23 on osteogenic differentiation was evaluated using alkaline phosphatase staining, alizarin red S staining and expression of bone formation-related proteins. Matrigel tube formation assay in vitro and immunofluorescence were used to detect the ability of FGF23 to affect endothelial cell angiogenesis. Steroids activated the pyroptosis signaling pathway, promoted the secretion of inflammatory factors in SONFH models, led to vascular endothelial dysfunction and damaged the femoral head structure. In addition, FGF23 inhibited the HUVECs angiogenesis and BMSCs osteogenic differentiation. FGF23 silencing attenuated steroid-induced osteonecrosis of the femoral head by inhibiting the pyroptosis signaling pathway, and promoting osteogenic differentiation of BMSCs and angiogenesis of HUVECs in vitro.

Dietary magnesium supplementation in cats with chronic kidney disease: A prospective double-blind randomized controlled trial.

BACKGROUND: Plasma total magnesium concentration (tMg) is a prognostic indicator in cats with chronic kidney disease (CKD), shorter survival time being associated with hypomagnesemia. Whether this risk factor is modifiable with dietary magnesium supplementation remains unexplored. OBJECTIVES: Evaluate effects of a magnesium-enriched phosphate-restricted diet (PRD) on CKD-mineral bone disorder (CKD-MBD) variables. ANIMALS: Sixty euthyroid client-owned cats with azotemic CKD, with 27 and 33 allocated to magnesium-enriched PRD or control PRD, respectively. METHODS: Prospective double-blind, parallel-group randomized trial. Cats with CKD, stabilized on a PRD, without hypermagnesemia (tMg >2.43 mg/dL) or hypercalcemia (plasma ionized calcium concentration, (iCa) >6 mg/dL), were recruited. Both intention-to-treat and per-protocol (eating ≥50% of study diet) analyses were performed; effects of dietary magnesium supplementation on clinicopathological variables were evaluated using linear mixed effects models. RESULTS: In the per-protocol analysis, tMg increased in cats consuming a magnesium-enriched PRD (ß, 0.25 ± .07 mg/dL/month; P < .001). Five magnesium supplemented cats had tMg >2.92 mg/dL, but none experienced adverse effects. Rate of change in iCa differed between groups (P = .01), with decreasing and increasing trends observed in cats fed magnesium-enriched PRD and control PRD, respectively. Four control cats developed ionized hypercalcemia versus none in the magnesium supplemented group. Log-transformed plasma fibroblast growth factor-23 concentration (FGF23) increased significantly in controls (ß, 0.14 ± .05 pg/mL/month; P = .01), but remained stable in the magnesium supplemented group (ß, 0.05±.06 pg/mL/month; P =.37). CONCLUSIONS AND CLINICAL IMPORTANCE: Magnesium-enriched PRD is a novel therapeutic strategy for managing feline CKD-MBD in cats, further stabilizing plasma FGF23 and preventing hypercalcemia.

Role of fibroblast growth factor-23 as an early marker of metabolic bone disease of prematurity.

PURPOSE: Metabolic bone disease of prematurity (MBDP) remains a significant cause of morbidity in extremely premature newborns. In high-risk patients, suspected diagnosis and subsequent treatment modifications, with limitations in terms of sensitivity and specificity, rely on low phosphorus levels and/or high levels of alkaline phosphatase (ALP). We investigated the potential of fibroblast growth factor-23 (FGF23) as an early marker for MBDP when measured at 3-4 weeks of life in at-risk patients. METHODS: A single-center prospective observational non-interventional study including preterm newborns of both sexes, with a gestational age of less than 32 weeks and/or a birth weight of less than 1500 g. In the standard biochemical screening for MBDP performed between 3 and 4 weeks of life within a nutritional profile, the determination of FGF23 was included along with other clinical and metabolic studies. The study was conducted at Marqués de Valdecilla University Hospital in Santander, Spain, from April 2020 to March 2021. Participants provided informed consent. Biochemical analyses were conducted using various platforms, and follow-up evaluations were performed at the discretion of neonatologists. Patients at high risk for MBDP received modifications in treatment accordingly. The sample was descriptively analyzed, presenting measures of central tendency and dispersion for continuous variables, and absolute numbers/percentages for categorical ones. Tests used included t-tests, Mann‒Whitney U tests, chi-square tests, logistic regressions, Pearson correlation, and ROC curve analysis (IBM SPSS Statistics version 19). Significance level: P < 0.05. RESULTS: In the study involving 25 at-risk premature newborns, it was found that 20% (n = 5) were diagnosed with MBDP. Three of these patients (60%) were identified as high-risk based on standard biochemical evaluation at 3-4 weeks of age, while the other two patients (40%) were diagnosed in subsequent weeks. However, in all 5 patients, measurement of FGF23 levels would allow for early identification and optimization of treatment before other markers become altered. Low levels of FGF23 at 3-4 weeks, even with normal phosphorus and ALP levels, indicate the need for modifications in nutritional supplementation. CONCLUSIONS: MBDP remains a significant concern in extremely premature newborns. Current diagnostic methods rely on limited biochemical markers. Early detection of low FGF23 levels enables timely interventions, potentially averting demineralization.

Comprehensive Molecular Characterization of a Large Series of Calcified Chondroid Mesenchymal Neoplasms Widening Their Morphologic Spectrum.

Recently, FN1 fusions to receptor tyrosine kinase genes have been identified in soft tissue tumors with calcified chondroid matrix named calcifying chondroid mesenchymal neoplasms (CCMNs). We collected 33 cases of CCMN from the French network for soft tissue and bone tumors. We performed whole-exome RNA sequencing, expression analysis, and genome-wide DNA methylation profiling in 33, 30, and 20 cases of CCMN compared with a control group of tumors, including noncalcified tenosynovial giant cell tumor (TGCT). Among them, 15 cases showed morphologic overlap with soft tissue chondroma, 8 cases with tophaceous pseudogout, and 10 cases with chondroid TGCT. RNA-sequencing revealed a fusion of FN1 in 76% of cases (25/33) with different 5' partners, including most frequently FGFR2 (14 cases), TEK or FGFR1. Among CCMN associated with FGFR1 fusions, 2 cases had overexpression of FGF23 without tumor-induced osteomalacia. Four CCMN had PDGFRA::USP8 fusions; 3 of which had histologic features of TGCT and were located in the hip, foot, and temporomandibular joint (TMJ). All cases with FN1::TEK fusion were located at TMJ and had histologic features of TGCT with or without chondroid matrix. They formed a distinct cluster on unsupervised clustering analyses based on whole transcriptome and genome-wide methylome data. Our study confirms the high prevalence of FN1 fusions in CCMN. In addition, through transcriptome and methylome analyses, we have identified a novel subgroup of tumors located at the TMJ, exhibiting TGCT-like features and FN1::TEK fusions.

Vitamin D3 suppresses Npt2c abundance and differentially modulates phosphate and calcium homeostasis in Npt2a knockout mice.

Vitamin D3 is clinically used for the treatment of vitamin D3 deficiency or osteoporosis, partially because of its role in regulating phosphate (Pi) and calcium (Ca2+) homeostasis. The renal sodium-phosphate cotransporter 2a (Npt2a) plays an important role in Pi homeostasis; however, the role of vitamin D3 in hypophosphatemia has never been investigated. We administered vehicle or vitamin D3 to wild-type (WT) mice or hypophosphatemic Npt2a-/- mice. In contrast to WT mice, vitamin D3 treatment increased plasma Pi levels in Npt2a-/- mice, despite similar levels of reduced parathyroid hormone and increased fibroblast growth factor 23. Plasma Ca2+ was increased ~ twofold in both genotypes. Whereas WT mice were able to increase urinary Pi and Ca2+/creatinine ratios, in Npt2a-/- mice, Pi/creatinine was unchanged and Ca2+/creatinine drastically decreased, coinciding with the highest kidney Ca2+ content, highest plasma creatinine, and greatest amount of nephrocalcinosis. In Npt2a-/- mice, vitamin D3 treatment completely diminished Npt2c abundance, so that mice resembled Npt2a/c double knockout mice. Abundance of intestinal Npt2b and claudin-3 (tight junctions protein) were reduced in Npt2a-/- only, the latter might facilitate the increase in plasma Pi in Npt2a-/- mice. Npt2a might function as regulator between renal Ca2+ excretion and reabsorption in response to vitamin D3.

Impact of Plant and Animal Protein-Based Meals on Serum Fibroblast Growth Factor-23 Levels in Healthy Young Men: A Randomized Crossover Trial.

Fibroblast growth factor-23 (FGF23) is a phosphaturic hormone secreted by osteocytes in response to dietary phosphate intake. An increase in FGF23 level is an indicator of excess phosphate intake relative to the residual nephron number. Therefore, avoiding excessive phosphate intake and inhibiting the elevation of serum FGF23 levels are important to preserve the number of functional nephrons. This randomized crossover trial aimed to determine the potential differences in the impacts on serum FGF23 levels between plant protein and animal protein-based meals in individuals with normal renal function. Nine young men were administered plant (no animal protein) or animal protein-based meals (70% of their protein was from animal sources) with the same phosphate content. The test meals consisted of breakfast, lunch, and dinner. Blood samples were collected in the morning, after overnight fasting, and before and after eating the test meals (for two consecutive days at the same hour each day). Furthermore, a 24-h urine sample was obtained on the day the test meal was consumed. No significant interactions were found among serum phosphate, calcium, and 1,25-dihydroxyvitamin D levels. However, after eating plant protein-based meals, serum FGF23 levels decreased and serum intact parathyroid hormone levels increased (interaction, p<0.05). Additionally, urine 24-h phosphate excretion tended to be lower in individuals consuming plant protein-based meals than in those consuming animal protein-based meals (p=0.06). In individuals with normal renal function, plant protein-based meals may prevent an increase in serum FGF23 levels and kidney damage caused by phosphate loading.

Role of signaling pathways in age-related orthopedic diseases: focus on the fibroblast growth factor family.

Fibroblast growth factor (FGF) signaling encompasses a multitude of functions, including regulation of cell proliferation, differentiation, morphogenesis, and patterning. FGFs and their receptors (FGFR) are crucial for adult tissue repair processes. Aberrant FGF signal transduction is associated with various pathological conditions such as cartilage damage, bone loss, muscle reduction, and other core pathological changes observed in orthopedic degenerative diseases like osteoarthritis (OA), intervertebral disc degeneration (IVDD), osteoporosis (OP), and sarcopenia. In OA and IVDD pathologies specifically, FGF1, FGF2, FGF8, FGF9, FGF18, FGF21, and FGF23 regulate the synthesis, catabolism, and ossification of cartilage tissue. Additionally, the dysregulation of FGFR expression (FGFR1 and FGFR3) promotes the pathological process of cartilage degradation. In OP and sarcopenia, endocrine-derived FGFs (FGF19, FGF21, and FGF23) modulate bone mineral synthesis and decomposition as well as muscle tissues. FGF2 and other FGFs also exert regulatory roles. A growing body of research has focused on understanding the implications of FGF signaling in orthopedic degeneration. Moreover, an increasing number of potential targets within the FGF signaling have been identified, such as FGF9, FGF18, and FGF23. However, it should be noted that most of these discoveries are still in the experimental stage, and further studies are needed before clinical application can be considered. Presently, this review aims to document the association between the FGF signaling pathway and the development and progression of orthopedic diseases. Besides, current therapeutic strategies targeting the FGF signaling pathway to prevent and treat orthopedic degeneration will be evaluated.

18F-AlF-NOTA-octreotide PET/CT in the localization of tumor-induced osteomalacia: case series and literature review.

Introduction: This study explores tumor-induced osteomalacia (TIO) through a case series and literature review, assessing the diagnostic potential of 18F-AlF-NOTA-octreotide (18F-OC) positron emission tomography/computed tomography (PET/CT). Methods: We analyzed TIO patients who underwent 18F-OC PET/CT. Parameters such as tumor dimension, the maximum standardized uptake value (SUVmax), the mean standardized uptake value (SUVmean) and metabolic tumor volume (MTV) were meticulously assessed. Clinical features and imaging characteristics pertinent to TIO were reviewed. Results: 6 patients with clinical suspicion of TIO exhibited hypophosphatemia (0.25 to 0.64 mmol/L), elevated alkaline phosphatase (ALP) levels (142 to 506 U/L), and increased parathyroid hormone (PTH) levels (92.9 to 281.7 pg/mL). Of these patients, two underwent FGF-23 testing, with results of 3185.00 pg/ml and 17.56 pg/ml, respectively. Conventional imaging modalities depicted widespread osteoporosis, with several cases demonstrating fractures indicative of osteomalacic and associated pathological fractures. Subsequent 18F-OC PET/CT facilitated the accurate localization of causative tumors, with histopathological examination confirming the diagnosis of phosphaturic mesenchymal tumor (PMT). The interval from initial clinical presentation to definitive TIO diagnosis spanned approximately 2.5 years (range: 1 - 4 years), with tumors varying in size (maximum diameter: 7.8 to 40.0 mm), SUVmax (5.47 to 25.69), SUVmean (3.43 to 7.26), and MTV (1.27 to 18.59 cm3). Conclusion: The implementation of whole-body 18F-OC PET/CT imaging emerges as a critical tool in the identification of occult tumors causing TIO. Future investigations incorporating a broader cohort are imperative to further delineate the diagnostic and therapeutic implications of 18F-OC PET/CT in managing TIO.

Preoperative inflammatory biomarkers reveal renal involvement in postsurgical mortality in hip fracture patients: an exploratory study.

Background: Hip fractures in frail patients result in excess mortality not accounted for by age or comorbidities. The mechanisms behind the high risk of mortality remain undetermined but are hypothesized to be related to the inflammatory status of frail patients. Methods: In a prospective observational exploratory cohort study of hospitalized frail hip fracture patients, 92 inflammatory markers were tested in pre-operative serum samples and markers were tested against 6-month survival post-hip fracture surgery and incidence of acute kidney injury (AKI). After correcting for multiple testing, adjustments for comorbidities and demographics were performed on the statistically significant markers. Results: Of the 92 markers tested, circulating levels of fibroblast growth factor 23 (FGF-23) and interleukin-15 receptor alpha (IL15RA), both involved in renal disease, were significantly correlated with 6-month mortality (27.5% overall) after correcting for multiple testing. The incidence of postoperative AKI (25.4%) was strongly associated with 6-month mortality, odds ratio = 10.57; 95% CI [2.76-40.51], and with both markers plus estimated glomerular filtration rate (eGFR)- cystatin C (CYSC) but not eGFR-CRE. The effect of these markers on mortality was significantly mediated by their effect on postoperative AKI. Conclusion: High postoperative mortality in frail hip fracture patients is highly correlated with preoperative biomarkers of renal function in this pilot study. The effect of preoperative circulating levels of FGF-23, IL15RA, and eGFR-CYSC on 6-month mortality is in part mediated by their effect on postoperative AKI. Creatinine-derived preoperative renal function measures were very poorly correlated with postoperative outcomes in this group.

Phosphocalcic metabolism and its potential association with biomarkers of kidney disease in dogs with spontaneous hyperadrenocorticism.

The pathogenesis of increased serum phosphate concentration and proteinuria in dogs with spontaneous hyperadrenocorticism (HAC) is unclear. A potential link between proteinuria and calcium/phosphate metabolism has never been studied in dogs with HAC. The aims of the study were: (1) To evaluate calcium/phosphate metabolism in dogs with spontaneous HAC and compare to healthy dogs as well as to dogs with non-HAC illness; (2) to look for associations between markers of calcium/phosphate metabolism and biomarkers of kidney disease in dogs with HAC. Fifty-four dogs were included in the study, classified as HAC (n=27), non-HAC disease (n=17), and healthy (n=10). Serum calcium, phosphate, 25(OH)Vitamin D, 1,25(OH)2Vitamin D, plasma intact parathyroid hormone concentration (iPTH), FGF23, and urinary fractional excretion of calcium and phosphate were evaluated in all dogs at diagnosis and compared between each group. The correlation between these variables and urine protein-to-creatinine ratio (UPC) and urinary N-acetylglucosaminidase-to-creatinine ratio (uNAG/C) was evaluated in the HAC group. Medians [range] of serum phosphate concentration, urinary fractional excretion of calcium (FE(Ca)), and iPTH were significantly higher in dogs with HAC than in dogs with non-HAC illness (P<0.01) and healthy dogs (P<0.01). Increased 1,25(OH)2Vitamin D/25(OH)Vitamin D was also observed (P<0.001). In HAC group, UPC was significantly negatively correlated with 25(OH)Vitamin D (r(s): -0.54; P<0.01). Urinary NAG/C was significantly positively correlated with serum phosphate (r(s): 0.46; P=0.019). Increased serum phosphate, urinary excretion of calcium, and hyperparathyroidism were observed in dogs with HAC. Vitamin D metabolism may be shifted towards increased 1-alpha hydroxylation.

Alterations in regulators of the renal-bone axis, inflammation and iron status in older people with early renal impairment and the effect of vitamin D supplementation.

CONTEXT: Chronic kidney disease (CKD) leads to alterations in fibroblast growth factor 23 (FGF23) and the renal-bone axis. This may be partly driven by altered inflammation and iron status. Vitamin D supplementation may reduce inflammation. OBJECTIVE AND METHODS: Older adults with early CKD (estimated glomerular filtration rate (eGFR) 30-60 ml/min/1.73 m2; CKDG3a/b; n = 35) or normal renal function (eGFR >90 ml/min/1.73 m2; CKDG1; n = 35) received 12,000, 24,000 or 48,000 IU D3/month for 1 year. Markers of the renal-bone axis, inflammation and iron status were investigated pre- and post-supplementation. Predictors of c-terminal and intact FGF23 (cFGF23; iFGF23) were identified by univariate and multivariate regression. RESULTS: Pre-supplementation, comparing CKDG3a/b to CKDG1, plasma cFGF23, iFGF23, PTH, sclerostin and TNFα were significantly higher and Klotho, 1,25-dihydroxyvitamin D and iron were lower. Post-supplementation, only cFGF23, 25(OH)D and IL6 differed between groups. The response to supplementation differed between eGFR groups. Only in the CKDG1 group, phosphate decreased, cFGF23, iFGF23 and procollagen type I N-propeptide increased. In the CKDG3a/b group, TNFα significantly decreased, and iron increased. Plasma 25(OH)D and IL10 increased, and carboxy-terminal collagen crosslinks decreased in both groups. In univariate models cFGF23 and iFGF23 were predicted by eGFR and regulators of calcium and phosphate metabolism at both time points; IL6 predicted cFGF23 (post-supplementation) and iFGF23 (pre-supplementation) in univariate models. Hepcidin predicted post-supplementation cFGF23 in multivariate models with eGFR. CONCLUSION: Alterations in regulators of the renal-bone axis, inflammation and iron status were found in early CKD. The response to vitamin D3 supplementation differed between eGFR groups. Plasma IL6 predicted both cFGF23 and iFGF23 and hepcidin predicted cFGF23.

S100a8/9 (S100 Calcium Binding Protein a8/9) Promotes Cardiac Hypertrophy Via Upregulation of FGF23 (Fibroblast Growth Factor 23) in Mice.

BACKGROUND: S100a8/9 (S100 calcium binding protein a8/9) belongs to the S100 family and has gained a lot of interest as a critical regulator of inflammatory response. Our previous study found that S100a8/9 homolog promoted aortic valve sclerosis in mice with chronic kidney disease. However, the role of S100a8/9 in pressure overload-induced cardiac hypertrophy remains unclear. The present study was to explore the role of S100a8/9 in cardiac hypertrophy. METHODS AND RESULTS: Cardiomyocyte-specific S100a9 loss or gain of function was achieved using an adeno-associated virus system, and the model of cardiac hypertrophy was established by aortic banding-induced pressure overload. The results indicate that S100a8/9 expression was increased in response to pressure overload. S100a9 deficiency alleviated pressure overload-induced hypertrophic response, whereas S100a9 overexpression accelerated cardiac hypertrophy. S100a9-overexpressed mice showed increased FGF23 (fibroblast growth factor 23) expression in the hearts after exposure to pressure overload, which activated calcineurin/NFAT (nuclear factor of activated T cells) signaling in cardiac myocytes and thus promoted hypertrophic response. A specific antibody that blocks FGFR4 (FGF receptor 4) largely abolished the prohypertrophic response of S100a9 in mice. CONCLUSIONS: In conclusion, S100a8/9 promoted the development of cardiac hypertrophy in mice. Targeting S100a8/9 may be a promising therapeutic approach to treat cardiac hypertrophy.

Genetic causes of hypophosphatemia.

Phosphate is a key component of mineralized tissues and is also part of many organic compounds. Phosphorus homeostasis depends especially upon intestinal absorption, and renal excretion, which are regulated by various hormones, such as PTH, 1,25-dihydroxyvitamin D, and fibroblast growth factor 23. In this review we provide an update of several genetic disorders that affect phosphate transporters through cell membranes or the phosphate-regulating hormones, and, consequently, result in hypophosphatemia.

A novel miR-466l-3p/FGF23 axis promotes osteogenic differentiation of human bone marrow mesenchymal stem cells.

BACKGROUND: MicroRNAs (miRNAs) regulate osteogenic differentiation processes and influence the development of osteoporosis (OP). This study aimed to investigate the potential role of miR-466 l-3p in OP. METHODS: The expression levels of miR-466 l-3p and fibroblast growth factor 23 (FGF23) were quantified in the trabeculae of the femoral neck of 40 individuals with or without OP using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The impact of miR-466 l-3p or FGF23 expression on cell proliferation and the expression levels of runt-related transcription factor 2 (RUNX2), type I collagen (Col1), osteocalcin (OCN), osterix (OSX) and dentin matrix protein 1 (DMP1) was quantified in human bone marrow mesenchymal stem cells (hBMSCs) overexpressing miR-466 l-3p. Furthermore, alkaline phosphatase (ALP) staining and alizarin red staining were performed to measure ALP activity and the levels of calcium deposition, respectively. In addition, bioinformatics analysis, luciferase reporter assays, and RNA pull-down assays were conducted to explore the molecular mechanisms underlying the effects of miR-466 l-3p and FGF23 in osteogenic differentiation of hBMSCs. RESULTS: The expression levels of miR-466 l-3p were significantly lower in femoral neck trabeculae of patients with OP than in the control cohort, whereas FGF23 levels exhibited the opposite trend. Furthermore, miR-466 l-3p levels were upregulated and FGF23 levels were downregulated in hBMSCs during osteogenic differentiation. Moreover, the high miR-466 l-3p expression enhanced the mRNA expression of RUNX2, Col1, OCN, OSX and DMP1, as well as cell proliferation, ALP activity, and calcium deposition in hBMSCs. FGF23 was found to be a direct target of miR-466 l-3p. FGF23 overexpression downregulated the expression of osteoblast markers and inhibited the osteogenic differentiation induced by miR-466 l-3p overexpression. qRT-PCR and Western blot assays showed that miR-466 l-3p overexpression decreased the expression levels of mRNAs and proteins associated with the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, whereas FGF23 upregulation exhibited the opposite trend. CONCLUSION: In conclusion, these findings suggest that miR-466 l-3p enhances the osteogenic differentiation of hBMSCs by suppressing FGF23 expression, ultimately preventing OP.

Tumour-induced osteomalacia: the long road to diagnosis and recovery.

Tumour-induced osteomalacia is caused by tumorous production of fibroblast growth factor 23 (FGF23) leading to urinary phosphate wasting, hypophosphataemia and decreased vitamin D activation. The resulting osteomalacia presents with muscle weakness and bone pain but progresses to multiple pathological fractures. Patients often remain undiagnosed for years with severe physical, psychological and economic ramifications. A young woman presented with multiple spontaneous fractures including bilateral femoral fractures. Laboratory tests revealed severe hypophosphataemia, elevated bone turnover markers and low to normal calcium and 25-hydroxy-vitamin D levels. Treatment with phosphate, alfalcalcidol, calcium and magnesium was initiated. 68Gallium-DOTATOC positron emission tomography imaging revealed a mass in the right foot and venous sampling of FGF23 from all extremities confirmed this tumour as the culprit. Biopsy and histology were consistent with a phosphaturic mesenchymal tumour, which was surgically resected. Phosphate levels quickly normalised postoperatively but a long convalescence with hungry bone syndrome, fracture healing and physical therapy followed.

A Rare Association Between Osteomalacia, Phosphaturic Mesenchymal Tumor, and Ovarian Cancer: A Case Report and Literature Review.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by hypophosphatemia, bone mineralization disorders with increased risk of fragility fractures, muscle pain, and progressive weakness. TIO has been associated with increased production of the phosphaturic hormone Fibroblast Growth Factor 23 (FGF23) usually by mesenchymal tumors of soft tissue or bone (Phosphaturic Mesenchymal Tumors-PMTs). In rare cases TIO may be observed in association with other malignancies. We report the case of a 66-year-old woman with an occasional diagnosis of both a PMT and an ovarian cancer during the evaluation of TIO. We also systematically review the literature to discover possible correlations between osteomalacia, FGF23 production, and ovarian cancer. Four studies were eligible for the analysis. Two case reports described an association between TIO development and ovarian cancer, whereas the two case-control studies hypothesized a possible correlation between FGF/FGF receptor axis and cancer development. Although it does not provide conclusive evidence regarding the association between TIO and ovarian cancer, this case report highlights the possibility that in the diagnostic workup of suspected TIO, both FGF23-secreting tumors distinct from PMT and tumors unrelated to the clinical presentation of TIO could be identified. This information is important for guiding successful tumor staging and determining the necessity for surgical intervention and/or eventual adjuvant therapy.

The endocrine FGFs axis: A systemic anti-fibrotic response that could prevent pulmonary fibrogenesis?

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease for which therapeutic options are limited, with an unmet need to identify new therapeutic targets. IPF is thought to be the consequence of repeated microlesions of the alveolar epithelium, leading to aberrant epithelial-mesenchymal communication and the accumulation of extracellular matrix proteins. The reactivation of developmental pathways, such as Fibroblast Growth Factors (FGFs), is a well-described mechanism during lung fibrogenesis. Secreted FGFs with local paracrine effects can either exert an anti-fibrotic or a pro-fibrotic action during this pathological process through their FGF receptors (FGFRs) and heparan sulfate residues as co-receptors. Among FGFs, endocrine FGFs (FGF29, FGF21, and FGF23) play a central role in the control of metabolism and tissue homeostasis. They are characterized by a low affinity for heparan sulfate, present in the cell vicinity, allowing them to have endocrine activity. Nevertheless, their interaction with FGFRs requires the presence of mandatory co-receptors, alpha and beta Klotho proteins (KLA and KLB). Endocrine FGFs are of growing interest for their anti-fibrotic action during liver, kidney, or myocardial fibrosis. Innovative therapies based on FGF19 or FGF21 analogs are currently being studied in humans during liver fibrosis. Recent data report a similar anti-fibrotic action of endocrine FGFs in the lung, suggesting a systemic regulation of the pulmonary fibrotic process. In this review, we summarize the current knowledge on the protective effect of endocrine FGFs during the fibrotic processes, with a focus on pulmonary fibrosis.