Identification Of Fibroblast Growth Factor Research Articles

Application of bioinformatics and molecular dynamics simulation approaches for identification of fibroblast growth factor 10 analogues with potentially improved thermostability

Fibroblast growth factor 10 functions as a paracrine mesenchymal molecule to initiate signalling pathways regarding to cellular development and health. However, the low thermal stability restricts it’s functionality in the human body and the shelf-life of FGF10-based formulations. The current study aimed to employ rational design and bioinformatics approaches to identify some point mutations which may improve the thermal stability of FGF10. Bioinformatics analyses resulted in N105D, C106F, K144R, K153M and I156R as the potential stability conferring mutations. The identified mutants were subjected to MD simulation indicating that all mutations are both structurally and energetically favoured. Finally, the effects of the identified mutations on receptor binding of FGF10 were predicted and the results showed that K144R and K153M mutations may increase the binding affinity relative to the wild type. The findings of the current study propose potentially improved FGF10 analogues for further experimental investigations.

Fibroblast Growth Factor 23 and Cardiovascular Outcome in Acute Kidney Injury

Even though the identification of Fibroblast Growth Factor 23 (FGF23) has been the breakthrough of the last decades in understanding mineral homeostasis, it is clear that it could have only been the starting point of an outstanding biomarker. This article focuses on available literature data concerning the increase of FGF23 in AKI and its potential influence upon associated or future to be cardiovascular disease.

Mitochondrial Respiratory Disorders: A Perspective on their Metabolite Biomarkers and Implications for Clinical Diagnosis and Therapeutic Intervention.

Mitochondrial respiratory disorders are incurable progressive degenerative diseases with multi-organ system manifestations. These orphan diseases are caused by mutations in the nuclear or mitochondrial genome affecting the oxidative phosphorylation (OXPHOS) system responsible for ATP synthesis. Currently, therapeutic treatments are not available to patients, resulting in significant disability and a poor prognosis. Patients exhibit a constellation of complex neurological and multisystem phenotypic symptoms. The hallmark of these diseases is their clinical heterogeneity and high variability among patients. Consequently, establishing an accurate diagnosis remains a challenging, invasive, and time-consuming process due to the limited sensitivity, specificity and reliability of the current serum biomarkers used in clinical settings. Recent mouse model-based research combined with patient studies led to the identification of fibroblast growth factor 21 (FGF-21) as a promising serum biomarker. With its high specificity and sensitivity, FGF-21 is a promising diagnostic tool for muscle-affecting mitochondrial respiratory disorders, which might be a useful first-line diagnostic tool instead of the invasive muscle biopsy currently performed in clinical settings. Discovering additional diagnostic biomarkers is critical for establishing an accurate diagnosis given the high clinical heterogeneity of these mitochondrial respiratory diseases. Ultimately, these novel biomarkers might be instrumental to monitor the progression of these diseases and the efficacy of novel therapeutic interventions.

Identification of fibroblast growth factor 15 as a novel mediator of liver regeneration and its application in the prevention of post-resection liver failure in mice

ObjectiveCholestasis is associated with increased liver injury and morbidity after partial hepatectomy (PH), yet bile acids (BAs) are emerging as important mediators of liver regeneration. Fibroblast growth factor 15 (Fgf15,...

FGF23: Is It Ready for Prime Time?

Since the identification of fibroblast growth factor 23 (FGF23)2 more than a decade ago, interest in this hormone has grown dramatically among both nephrologists and endocrinologists. FGF23, initially identified in patients with rare forms of hypophosphatemia, is also increased in patients with chronic kidney disease (CKD). A handful of studies have suggested that increased circulating concentrations of FGF23 not only play an important role in the development of secondary hyperparathyroidism but also are associated with adverse systemic effects, including increased mortality and deterioration of renal function—associations that have definitively been confirmed in a new prospective study of 3879 adult patients with CKD (1). Isakova et al. reported that circulating FGF23 concentrations were an independent predictor, over a 5-year period, of both ( a ) progression to end-stage renal disease in patients with a baseline estimated glomerular filtration rate >30 mL · min−1 · (1.73 m2)−1 and ( b ) mortality in patients with predialysis CKD. These findings highlight the systemic importance of FGF23 and raise the question of whether FGF23 measurements should now be considered a clinically useful biomarker for diagnosing and managing CKD mineral and bone disorder (CKD-MBD). Current algorithms for the diagnosis and treatment of CKD-MBD recommend periodic measurement of creatinine, calcium, phosphorus, alkaline phosphatase, parathyroid hormone, and 25-hydroxyvitamin D concentrations in the plasma of patients at all stages of CKD. These biochemical variables are markers of altered mineral, bone, and/or vascular metabolism. FGF23 measurements, however, are not currently recommended by any guidelines, nor are they available in most clinical laboratories. Although the report by Isakova et al.(1) suggests that increased circulating FGF23 concentrations do predict mortality in patients with CKD, several major hurdles …

Identification of fibroblast growth factor 1 (FGF‐1) in a black market product

The use of growth factors for accelerated healing of sports injuries is restricted under the terms of the World Anti-Doping Agency (WADA) anti-doping code. Cheating athletes have used the black market as a source of performance-enhancing substances. Drugs that currently undergo clinical trials are frequently offered--despite the unknown health risks associated with the administration of unapproved pharmaceuticals. Recently, a new growth factor (referred to as fibroblast growth factor 1/FGF-1) with known effects on the repair and regeneration of damaged tissue was detected in an unlabelled black market product confiscated by the German customs. The identification of the protein was achieved by one- and two-dimensional polyacrylamide gel electrophoresis (SDS-PAGE and 2D-PAGE), different proteolytic digestions, immunological methods and nano-liquid chromatography high-resolution/high-accuracy Orbitrap mass spectrometry. The SDS-PAGE analysis revealed slight differences concerning the molecular weight of recombinant human and black market FGF-1. Using in-gel proteolysis, a truncation or modification located at the N-terminus of the protein was suggested. These findings demonstrate that drug candidates without clinical approval can be readily obtained from the black market, regardless of potential dangerous consequences for the consumer, which corroborates the necessity of proactive and preventive doping control approaches. In that regard, physiological concentrations of blood and urine specimens collected from healthy individuals were analyzed and were found to range below 28 pg/ml in urine, while there was no detectable FGF-1 in plasma.

Three feedback loops precisely regulating serum phosphate concentration

Parathyroid hormone (PTH) and vitamin D were considered the major factors regulating phosphate homeostasis. Now, with the identification of fibroblast growth factor 23 (FGF23), a phosphaturic molecule inhibiting calcitriol and PTH, they need to be integrated into three feedback loops involving parathyroid, bone, and kidney. PTH and calcitriol are required for the appropriate synthesis of FGF23 by bone cells. PTH also regulates klotho expression in the kidney and thereby the phosphaturic action of FGF23.

Fibroblast Growth Factor, A Review

The recent identification of fibroblast growth factor (FGF)23 has filled in the gaps of our understanding of calcium– phosphate regulation. Together with its cofactor Klotho, FGF-23 is a phosphaturic factor that influences vitamin D metabolism and renal re-absorption of phosphorus in order to maintain serum phosphate levels within the normal range. In chronic kidney disease (CKD), FGF-23 levels rise in parallel with declining kidney function before any significant rise is perceived in serum phosphate concentration. Increased serum FGF-23 levels in CKD patients were found to be independently associated with ventricular hypertrophy and endothelial dysfunction after correcting for traditional markers of calcium–phosphate metabolism. FGF-23 has been implicated in various human diseases including autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemia (XLH), tumor induced osteomalacia and familial tumoral calcinosis. Lastly, in prospective studies, elevated serum FGF-23 levels predicted rapid disease progression in non-dialysis dependent CKD patients and increased mortality in chronic hemodialysis patients. The growing knowledge and understanding of FGF-23 may provide potential answers with regards to prevention and management of CKD [1]. The FGF family is comprised of polypeptides that share a common region of amino peptide residues. Seven human FGF subfamilies have been identified; FGF-23 belongs to the FGF19 subgroup including FGF 19, 21 and 23 having very different physiological functions despite sharing a similar disulphide bond which is absent in most other families. FGF23 is a central regulator of phosphate homeostasis, enhancing phosphorus excretion and suppressing1-alpha hydroxylase activity in the kidney [2, 3], whereas FGF-19 is involved in bile acid synthesis and FGF-21 stimulates insulinindependent glucose uptake in adipocytes and reduces triglyceride levels. The active form of FGF-23 is an approximately 32-kD (251 amino acids) protein with its gene located on chromosome 12 [4, 5]. It is mainly expressed in osteocytes [6, 7], and also expressed in pericyte-like cells around the venous sinuses, the ventrolateral thalamic nucleus, and in the thymus. The contribution of sites other than bone to circulating FGF-23 levels is still unclear. It is clear, however that there are high levels of expression in the osteocytes and that because osteocytes are the most abundant cell in bone, this suggests that the serum levels of FGF-23 are derived mainly from bone [8]. FGF-23 exerts its biological effects through activation of FGF receptors in a Klotho dependent manner, as a Klotho/ FGF-Receptor complex binds to FGF-23. Klotho is a transmembrane protein, the gene expression of which was detected in distal renal tubular cells, parathyroid gland, the pituitary gland, ovary, testis, skeletal muscle, duodenum, pancreas and choroid plexus. It is unclear why Klotho is G. C. Chibesakunda (*) :C. S. Brecklin Department of Medicine/Section of Nephrology, University of Illinois Medical Center at Chicago, 820 S Wood Street (MC 793), Chicago, IL 60612, USA e-mail: gracecc@uic.edu

Le facteur de croissance des fibroblastes 23 et son récepteur Klotho

The kidney is a key player of phosphate balance, it determines serum phosphate levels by coupling phosphate reabsorption in the renal proximal tubule, calcitriol synthesis and consequently intestinal -phosphate absorption. The identification of fibroblast growth factor 23 (FGF23) as a hormone regulating phosphate and calcitriol metabolism has unveiled the mechanisms that coordinate these renal proximal tubule functions. A bone-kidney axis has emerged that controls bone mineralization. Animal model studies have improved our understanding of phosphate homeostasis and revealed the role of the Klotho protein, which is mandatory to FGF23 action. In this review, we detail FGF23 and Klotho implication in physiology and in genetic or acquired disorders. Phosphate ion is involved in vascular and soft tissue calcification and is important for cell proliferation. Disorders of FGF23-klotho axis alter life span and are involved in senescence.

Latest findings in phosphate homeostasis

The kidney is a key player in phosphate balance. Inappropriate renal phosphate transport may alter serum phosphate concentration and bone mineralization, and increase the risk of renal lithiasis or soft tissue calcifications. The recent identification of fibroblast growth factor 23 (FGF23) as a hormone regulating phosphate and calcitriol metabolism and of klotho has changed the understanding of phosphate homeostasis; and a bone-kidney axis has emerged. In this review, we present recent findings regarding the consequences of mutations affecting several human genes encoding renal phosphate transporters or proteins regulating phosphate transport activity. We also describe the role played by the FGF23-klotho axis in phosphate homeostasis and its involvement in the pathophysiology of phosphate disturbances in chronic kidney disease.

Fibroblast growth factor 23–Klotho : un nouvel axe de régulation du bilan du phosphate

The kidney is a key player of phosphate balance, it determines serum phosphate levels by coupling phosphate reabsorption in the renal proximal tubule, calcitriol synthesis and consequently intestinal phosphate absorption. The identification of fibroblast growth factor 23 (FGF23) as a hormone regulating phosphate and calcitriol metabolism has unveiled the mechanisms that coordinate these renal proximal tubule functions. A bone–kidney axis has emerged that controls bone mineralization. Animal model studies have improved our understanding of phosphate homeostasis and revealed the role of the protein Klotho, which is mandatory to FGF23 action. In this review we detail FGF23 and Klotho implications in physiology and in genetic or acquired disorders. Phosphate ion is involved in vascular and soft tissue calcification and is important for cell proliferation. Disorders of FGF23–Klotho axis alter life-span and the survival in some cancers.