Role Of Fibroblast Growth Factor Research Articles

The role of fibroblast growth factor 23 in regulation of phosphate balance.

Phosphate is essential for numerous biological processes, and serum levels are tightly regulated to accomplish these functions. The regulation of serum phosphate in a narrow physiological range is a well-orchestrated process and involves the gastrointestinal (GI) tract, bone, kidneys, and several hormones, namely, parathyroid hormone, fibroblast growth factor 23 (FGF23), and 1,25-dihydroxyvitamin D (1,25 Vitamin D). Although primarily synthesized in the bone, FGF23, an endocrine FGF, acts on the kidney to regulate phosphate and Vitamin D homeostasis by causing phosphaturia and reduced levels of 1,25 Vitamin D. Recent studies have highlighted the complex regulation of FGF23 including transcriptional and post-translational modification and kidney-bone cross talk. Understanding FGF23 biology has led to the identification of novel therapeutic agents to treat diseases that disrupt phosphate metabolism secondary to FGF23. The focus of this review is to provide an overview of phosphate homeostasis, FGF23 biology, and the role of FGF23 in phosphate balance.

Fibroblast growth factor 21 (FGF21): diagnostic, prognostic and therapeutic aspects in heart failure. A review

Chronic heart failure (CHF) is a global medical, social and economic problem. Currently, the search and study of new biomarkers that can provide early diagnosis of CHF, serve as a laboratory tool for assessing the effectiveness of treatment, or be used as prognostic markers and risk stratification criteria are ongoing. Scientists' interest is focused, in particular, on studying the role of fibroblast growth factor 21 (FGF21) in CHF. There is increasing evidence highlighting the value of FGF21 as a new marker for the diagnosis and assessment of prognosis in patients with CHF. The role of FGF21 in CHF is very interesting due to its cardioprotective aspects. Final confirmation of the diagnostic, prognostic and therapeutic roles of FGF21 will come from future studies.

Non-Classical Effects of FGF23: Molecular and Clinical Features.

This article reviews the role of fibroblast growth factor 23 (FGF23) protein in phosphate metabolism, highlighting its regulation of vitamin D, parathyroid hormone, and bone metabolism. Although it was traditionally thought that phosphate-calcium homeostasis was controlled exclusively by parathyroid hormone (PTH) and calcitriol, pathophysiological studies revealed the influence of FGF23. This protein, expressed mainly in bone, inhibits the renal reabsorption of phosphate and calcitriol formation, mediated by the α-klotho co-receptor. In addition to its role in phosphate metabolism, FGF23 exhibits pleiotropic effects in non-renal systems such as the cardiovascular, immune, and metabolic systems, including the regulation of gene expression and cardiac fibrosis. Although it has been proposed as a biomarker and therapeutic target, the inhibition of FGF23 poses challenges due to its potential side effects. However, the approval of drugs such as burosumab represents a milestone in the treatment of FGF23-related diseases.

Emerging concepts on the FGF23 regulation and activity.

Fibroblast growth factor 23 (FGF23) discovery has provided new insights into the regulation of Pi and Ca homeostasis. It is secreted by osteoblasts and osteocytes, and acts mainly in the kidney, parathyroid, heart, and bone. The aim of this review is to highlight the current knowledge on the factors modulating the synthesis of FGF23, the canonical and non-canonical signaling pathways of the hormone, the role of FGF23 in different pathophysiological conditions, and the anti-FGF23 therapy. This is a narrative review based on the search of PubMed database in the range of years 2000-2023 using the keywords local and systemic regulators of FGF23 synthesis, FGF23 receptors, canonical and non-canonical pathways, pathophysiological conditions and FGF23, and anti-FGF23 therapy, focusing the data on the molecular mechanisms. The regulation of FGF23 synthesis is complex and multifactorial. It is regulated by local factors and systemic regulators mainly involved in bone mineralization. The excessive FGF23 production is associated with different congenital diseases and with diseases occurring with a secondary high FGF23 production such as in chronic disease kidney and tumor-induced osteomalacia (TIO). The anti-FGF23 therapy appears to be useful to treat chromosome X-linked hypophosphatemia and TIO, but there are doubts about the handle of excessive FGF23 production in CKD. FGF23 biochemistry and pathophysiology are generating a plethora of knowledge to reduce FGF23 bioactivity at many levels that might be useful for future therapeutics of diseases associated with high-serum FGF23 levels.

Is fibroblast growth factor 11 (FGF11) a predictive marker for breast cancer?

The prognostic role of fibroblast growth factor 11 (FGF11) has only been reported in cancers such as nasopharyngeal carcinoma and prostate cancer. The role of FGF11 in breast cancer is not fully known. It was aimed to compare FGF11 expression levels in de novo metastatic hormone receptor-positive, human epidermal reseptor-2-negative breast tumor tissue and healthy breast tissue and investigate the effect of the FGF11 expression on survival in breast cancer patients. To determine the FGF11 expression rate, breast tumor tissue of breast cancer patients diagnosed by breast biopsy and healthy breast tissue of healthy individuals who underwent breast biopsy due to benign lesions were used. The study population included 38 breast cancer patients and 24 healthy controls. The number of patients with a FGF11 expression level score of 1 (15.8% vs 12.5%), score of 2 (18.4% vs 12.5%), and score of 3 (31.6% vs 0%) was significantly higher in the patient group compared to the healthy control group. The median overall survival and progression-free survival were numerically better in the group with a FGF11 expression score of 0 to 1 than the group with a FGF11 expression score of 2 and 3, but this difference was not statistically significant. FGF11 may be a predictive marker for breast cancer formation. Additionally, with new FGF11-targeted treatment agents to be developed, endocrine resistance may be reduced, and better survival results may be achieved in hormone receptor-positive, human epidermal reseptor-2-negative breast cancer.

The prognostic significance of fibroblast growth factor-23 in predicting complications of type 2 diabetes mellitus, especially when associated with obesity

type 2 Diabetes Mellitus (T2DM) is considered a global health problem with an exceptionally high economic burden not only for families but also for countries overall. In 90-95% of T2DM cases, varying degrees of obesity are observed. One aspect contributing to complications in T2DM involves musculoskeletal system impairment, specifically alterations in bone mineral density (BMD), indicative of bone architecture disruption, leading to secondary osteoporotic conditions. Fibroblast growth factors (FGFs), known for their regulatory influence on metabolism, are identified as mechanisms activated in T2DM. Within this group, fibroblast growth factor 23 (FGF-23) is acknowledged. In individuals with T2DM and excess weight or obesity, conditions conducive to increased FGF-23 synthesis are established, contributing to disturbances in mineral metabolism. Therefore, our study aimed to investigate the content and role of FGF-23 in the development of secondary osteoporosis in T2DM patients with concurrent obesity. A total of 103 patients with type 2 diabetes were involved, with 83 cases featuring elevated body weight or obesity (main group). To assess the impact of obesity on FGF-23 changes, a comparison group of 20 T2DM patients with normal body weight (NBW) was formed. The average age of patients with comorbid conditions was 43±4.6 years, and for those with isolated T2DM, it was 44.1±2.1 years. The average duration of T2DM across groups ranged from 1 to 13 years (6.7±2.4 years on average). Control FGF-23 values were obtained from a group of 20 practically healthy individuals of similar age and gender. The diagnosis of T2DM was confirmed according to the Unified Medical Assistance Protocol "Diabetes Mellitus" (Order of the Ministry of Health of Ukraine dated December 21, 2012, No. 1118). Thus, all examined T2DM patients were in the subcompensation stage with a moderate degree of disease severity. The presence and severity of obesity were assessed according to the International Diabetes Federation (IDF, 2005) criteria based on the body mass index (BMI) calculation using the Ketle formula. In the examination of 83 T2DM patients with obesity, a probable increase in fibroblast growth factor 23 (FGF-23) in serum was determined, correlating with osteoporotic changes in dual-energy X-ray absorptiometry. Therefore, FGF-23 can be utilized as a marker for bone mineral density status and control of treatment measures.

Roles of fibroblast growth factors in the treatment of diabetes.

Diabetes affects about 422 million people worldwide, causing 1.5 million deaths each year. However, the incidence of diabetes is increasing, including several types of diabetes. Type 1 diabetes (5%-10% of diabetic cases) and type 2 diabetes (90%-95% of diabetic cases) are the main types of diabetes in the clinic. Accumulating evidence shows that the fibroblast growth factor (FGF) family plays important roles in many metabolic disorders, including type 1 and type 2 diabetes. FGF consists of 23 family members (FGF-1-23) in humans. Here, we review current findings of FGFs in the treatment of diabetes and management of diabetic complications. Some FGFs (e.g., FGF-15, FGF-19, and FGF-21) have been broadly investigated in preclinical studies for the diagnosis and treatment of diabetes, and their therapeutic roles in diabetes are currently under investigation in clinical trials. Overall, the roles of FGFs in diabetes and diabetic complications are involved in numerous processes. First, FGF intervention can prevent high-fat diet-induced obesity and insulin resistance and reduce the levels of fasting blood glucose and triglycerides by regulating lipolysis in adipose tissues and hepatic glucose production. Second, modulation of FGF expression can inhibit renal and cardiac fibrosis by regulating the expression of extracellular matrix components, promote diabetic wound healing process and bone repair, and inhibit cancer cell proliferation and migration. Finally, FGFs can regulate the activation of glucose-excited neurons and the expression of thermogenic genes.

ERRγ-inducible FGF23 promotes alcoholic liver injury through enhancing CYP2E1 mediated hepatic oxidative stress

Fibroblast growth factor 23 (FGF23) is a member of endocrine FGF family, along with FGF15/19 and FGF21. Recent reports showed that under pathological conditions, liver produces FGF23, although the role of hepatic FGF23 remains nebulous. Here, we investigated the role of hepatic FGF23 in alcoholic liver disease (ALD) and delineated the underlying molecular mechanism. FGF23 expression was compared in livers from alcoholic hepatitis patients and healthy controls. The role of FGF23 was examined in hepatocyte-specific knock-out (LKO) mice of cannabinoid receptor type 1 (CB1R), estrogen related receptor γ (ERRγ), or FGF23. Animals were fed with an alcohol-containing liquid diet alone or in combination with ERRγ inverse agonist. FGF23 is mainly expressed in hepatocytes in the human liver, and it is upregulated in ALD patients. In mice, chronic alcohol feeding leads to liver damage and induced FGF23 in liver, but not in other organs. FGF23 is transcriptionally regulated by ERRγ in response to alcohol-mediated activation of the CB1R. Alcohol induced upregulation of hepatic FGF23 and plasma FGF23 levels is lost in ERRγ-LKO mice, and an inverse agonist mediated inhibition of ERRγ transactivation significantly improved alcoholic liver damage. Moreover, hepatic CYP2E1 induction in response to alcohol is FGF23 dependent. In line, FGF23-LKO mice display decreased hepatic CYP2E1 expression and improved ALD through reduced hepatocyte apoptosis and oxidative stress. We recognized CBIR-ERRγ-FGF23 axis in facilitating ALD pathology through hepatic CYP2E1 induction. Thus, we propose FGF23 as a potential therapeutic target to treat ALD.

FGF23 facilitates IL-1β synthesis in rheumatoid arthritis through activating PI3K, Akt, and NF-κB pathways.

Rheumatoid arthritis (RA) is a well-known autoimmune disorder related with joint pain, joint swelling, cartilage and bone degradation as well as deformity. Fibroblast growth factor 23 (FGF23) is an endocrine factor of the FGF family primarily produced by osteocytes and osteoblasts, involves an essential effect in pathogenesis of RA. IL-1β is a vital proinflammatory factor in the development of RA. However, the role of FGF23 on IL-1β synthesis in RA has not been fully explored. Our analysis of database revealed higher levels of FGF23 and IL-1β in RA samples compared with healthy controls. High-throughput screening demonstrated that IL-1β is a potential candidate factor after FGF23 treatment in RA synovial fibroblasts (RASFs). FGF23 concentration dependently promotes IL-1β synthesis in RASFs. FGF23 enhances IL-1β expression by activating the PI3K, Akt, and NF-κB pathways. Our findings support the notion that FGF23 is a promising target in the remedy of RA.

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.

The role of fibroblast growth factor-2 in the development of bronchopulmonary dysplasia in very and extremely low birth weight infants

Introduction and objective: The aim of the study was to assess the association between serum levels of fibroblast growth factor-2 (FGF-2) in infants in the first week of life and the risk of developing bronchopulmonary dysplasia. Materials and methods: The study included 103 infants, born before 32 weeks of gestation with a birth weight ≤1,500 g. Serum FGF-2 levels were measured in all newborns on days 1 and 7 of life. Results: Analysing the dynamics of changes in serum FGF-2 level, a statistically significant positive correlation was observed for birth weight (R = 0.20, p = 0.0423) in the first week of life. However, no statistically significant correlation was found for gestational age (R = 0.06, p = 0.5146). Infants with bronchopulmonary dysplasia had significantly lower gestational age than those without bronchopulmonary dysplasia (p < 0.0001) and birth weight (p < 0.0001). No statistically significant correlation was found between the dynamics of changes in serum FGF-2 level in the first week of life and the risk of bronchopulmonary dysplasia development for the definition of bronchopulmonary dysplasia on day 28 of life (p = 0.5330), and for the definition as the need for supplemental oxygen and/or respiratory support at 36 weeks of postmenstrual age (p = 0.7914). Conclusions: The study found no association between the serum FGF-2 level in the first week of life and the risk of bronchopulmonary dysplasia development in infants born before 32 weeks of gestation with a birth weight ≤1,500 g. In the study group, a statistically significant positive correlation was found for birth weight. In our study, gestational age and birth weight were found to be among the major risk factors for the development of bronchopulmonary dysplasia.

Suppression of BMP signaling restores mitral cell development impaired by FGF signaling deficits in mouse olfactory bulb

Fibroblast growth factors (FGFs) and bone morphogenic proteins (BMPs) play various important roles in the development of the central nervous system. However, the roles of FGF and BMP signaling in the development of the olfactory bulb (OB) are largely unknown. In this study, we first showed the expression of FGF receptors (FGFRs) and BMP receptors (BMPRs) in OB RGCs, radial glial cells (RGCs) in the developing OB, which generate the OB projection neurons, mitral and tufted cells. When the FGF signaling was inhibited by a dominant-negative form of FGFR1 (dnFGFR1), OB RGCs accelerated their state transition to mitral cell precursors without affecting their transcription cascade and fate. However, the mitral cell precursors could not radially migrate to form the mitral cell layer (MCL). In addition, FGF signaling inhibition reduced the expression of a BMP antagonist, Noggin, in the developing OB. When BMP signaling was suppressed by the ectopic expression of Noggin or a dominant-negative form of BMPR1a (dnBMPR1a) in the developing OB, the defect in MCL formation caused by the dnFGFR1 was rescued. However, the dnBMPR1a did not rescue the accelerated state transition of OB RGCs. These results demonstrate that FGF signaling is important for OB RGCs to maintain their self-renewal state and MCL formation. Moreover, the suppression of BMP signaling is required for mitral cells to form the MCL. This study sheds new light on the roles of FGFs and BMPs in OB development.

FGF2 promotes the chemotherapy resistance in colon cancer cells through activating PI3K/Akt signaling pathway

Abstract Background To investigate the role of fibroblast growth factor 2 (FGF2) in chemotherapy resistance of colon cancer. Methods An HCT116/5-fluorouracil (5-FU)–resistant cell line was established, and FGF2 levels were detected in a sensitive cell group (HCT116) and a resistant cell group (HCT1116-R) using different methods. Fibroblast growth factor 2 levels in the medium were determined by enzyme-linked immunoassay. The protein expressions of FGF2, fibroblast growth factor receptor 1 (FGFR1), and phospho-FGFR1 were assessed by Western blotting, and FGF2 mRNA levels were detected by quantitative real-time polymerase chain reaction. Fibroblast growth factor 2 recombinant protein was added to sensitive cells, and FGFR inhibitor AZD4547 was added to resistant cells, and the cell survival rate was determined using the cell counting kit-8 method and the protein expressions of PI3K (phosphatidylinositol 3 kinase), p-PI3K (phospho-PI3K), Akt (protein kinase B), p-Akt (phospho-Akt), mammalian target of rapamycin (mTOR), p-mTOR (phospho-mTOR), Bad (Bcl-xL/Bcl-2–associated death promoter), NF-κB (nuclear factor κB), GSK-3 (glycogen synthase kinase-3), FKHR (forkhead box protein O1), and PTEN (phosphatase and tensin homolog deleted on chromosome ten) were detected by Western blotting. Results Fibroblast growth factor 2 protein and mRNA expression levels in the HCT116-R group were significantly higher than those in the HCT116 group. Fibroblast growth factor 2 increased the survival rate of HCT116 cells; improved tolerance to 5-FU; upregulated p-PI3K, p-Akt, and p-mTOR; and downregulated Bad. The FGFR inhibitor AZD4547 decreased cell survival rate and tolerance to 5-FU; downregulated p-PI3K, p-Akt, and p-mTOR expression; and upregulated Bad. Conclusions Fibroblast growth factor 2 promotes chemotherapy tolerance in colon cancer cells by activating the Akt/mTOR and Akt/Bad signaling pathways downstream of PI3K.

Fibroblast growth factor 23 is a strong independent marker of poor outcome after an acute coronary syndrome

Abstract Our study aimed to assess the role of fibroblast growth factor 23 (FGF-23) as a prognostic marker after an acute coronary syndrome (ACS). It was a prospective and multicentric study, performed at five tertiary hospitals in our city, which included 1,190 patients with ACS. FGF-23 plasma levels and other components of mineral metabolism (calcidiol, parathormone [PTH], klotho, and phosphate), lipids, troponin, high-sensitivity C-reactive protein, and N-terminal-pro-brain natriuretic peptide were measured at discharge. The primary outcome was a combination of acute ischemic events, heart failure (HF) and death. Secondary outcomes were the separate components of the primary outcome. Median follow-up was 5.44 (3.03-7.46) years. 294 patients developed the primary outcome. Patients with FGF-23 less than median (which was settled in 110 RU/mL) were less frequently females, and were younger and had a lower load of cardiovascular risk factors. Besides, calcidiol and PTH levels were lower in patients with FGF-23 below the median. Multivariable analysis showed that FGF-23 (HR 1.18 [1.08-1.29], p<0.001), calcidiol (HR 0.86 [0.74-1.00], p=0.046), previous CAD or cerebrovascular accident, and hypertension were independent predictors of the primary outcome. The predictive power of FGF-23 was homogeneous across different subgroups of population. FGF-23 resulted an independent predictor of HF (HR 1.38 [1.22-1.57], p<0.001), and death (HR 1.21 [1.07-1.37], p=0.002), but not of acute ischemic events. According to renal function, FGF-23 was an independent predictor for the primary outcome in patients with estimated glomerular filtration rate (eGFR) above 60 ml/min/1.73m2,, showing that the potential prognostic role of FGF-23 was not exclusively related to chronic kidney disease patients. Moreover, regarding the secondary outcomes, FGF-23 resulted an independent predictor of HF and death. To sum up, FGF-23 seems to be a strong, independent, predictor of HF and death among patients with ACS. This effect is homogeneous across different subgroups of population and not limited to patients with CKD.

FGF23 Inhibition Improves Hematopoietic Stem Cell Transplantation in β-Thalassemia

Clinical evidence has established a link between anemias and skeletal abnormalities, although the underlying molecular mechanisms remain elusive. β-thalassemia (βThal) represents a valuable model for studying congenital anemia and associated bone and bone marrow (BM) microenvironment defects. Osteoporosis has a high morbidity in βThal patients, and we demonstrated that impaired hematopoietic stem cell (HSC) function is due to the prolonged persistence in an altered βThal BM niche ( Aprile et al, 2020). The correction of the genetic cause of βThal, mutations in the β-globin gene, is achieved by transplantation of HSCs from healthy donors or autologous HSCs from patients upon gene therapy. In both scenarios, a comprehensive understanding of HSCs and the BM niche is crucial to obtain successful outcomes. Our research focused on the role of fibroblast growth factor 23 (FGF23), a phosphaturic hormone at the crossroads of bone and erythropoiesis. We demonstrated that the elevated erythropoietin characteristic of the disease, leads to increased FGF23 production in both the βThal mouse model ( th3) and βThal patients, negatively affecting bone homeostasis and the interaction between HSCs and the stromal niche. Notably, in vivo FGF23 inhibition by cFGF23 peptide in th3 mice fully rescued bone defects, BM niche and HSC function ( Aprile, Raggi et al, 2023). To mimic the allogenic transplantation, we transplanted wt and th3 cells in a competitive setting into untreated th3 or th3+cFGF23 recipients. We observed partially enhanced engraftment in the cFGF23-treated mice indicating that FGF23 inhibition improves the supportive capacity of the damaged niche. We hypothesized that prolonged cFGF23 administration to recipient mice after transplantation could further restore the BM niche and boost the graft, thus achieving therapeutic outcomes. To establish the proper dose regimen with withdrawal periods for prolonged cFGF23 treatment, we analyzed bone mineral density (BMD) and HSC cell cycle at 1 and 2 weeks after discontinuing cFGF23 administration. Our results showed that rescued BMD was sustained after the discontinuation of treatment for 1 and 2 weeks ( th3 vs. th3+cFGF23 _1wk vs. th3+cFGF23_2wks: 125.9±3.8 vs. 181±19.9 vs. 142±1.6 mg/cm 3, p<0.01). Ongoing histomorphometric analysis will provide a better characterization of bone quality. Additionally, we observed the restoration of defective quiescence in th3 HSCs after 1- and 2 weeks ( th3 vs. th3+cFGF23 _1wk vs. th3+cFGF23_2wks: 77.8±1,4 vs. 92.1±1.8 vs. 87.8±0.9 on Lin neg BM cells, p<0.001). To test autologous transplantation upon gene therapy, we transduced th3 Lin neg BM cells with a lentiviral vector carrying the β-globin gene (GLOBE LV) at MOI 5 resulted in a mean vector copy number of 1 and a transduction efficiency of 50%. We performed competitive transplantation using 1x10 5 (CD45.1) transduced donor th3 cells and 1x10 5 (CD45.2) competitor mock-transduced th3 cells into busulfan-conditioned (CD45.2) untreated th3 or th3+cFGF23 recipient mice. The treated recipient mice received two doses of cFGF23 every 2 weeks as a maintenance regimen. We observed higher engraftment of transduced cells in the peripheral blood of cFGF23-treated mice at 8 weeks post-transplant ( th3 vs. th3+cFGF23: 4.9±1.1 vs. 10.7±1.9 % of CD45.1 engrafted cells, p<0.05). Comparative evaluation of hematological parameters and molecular analysis of transduced cells are ongoing. Targeting FGF23 signaling provides a promising strategy to improve bone defects and HSC-niche alterations in βThal. Here, we show that the use of FGF23 inhibition in the transplantation setting in β-thalassemia results in superior engraftment of donor cells in treated recipients, indicating a potential application to ameliorate the clinical outcome.

The Comparison of Commercial Serum-Free Media for Hanwoo Satellite Cell Proliferation and the Role of Fibroblast Growth Factor 2.

Fetal bovine serum (FBS), which contains various nutrients, comprises 20% of the growth medium for cell-cultivated meat. However, ethical, cost, and scientific issues, necesitates identification of alternatives. In this study, we investigated commercially manufactured serum-free media capable of culturing Hanwoo satellite cells (HWSCs) to identify constituent proliferation enhancing factors. Six different serum-free media were selected, and the HWSC proliferation rates in these serum-free media were compared with that of control medium supplemented with 20% FBS. Among the six media, cell proliferation rates were higher only in StemFlexTM Medium (SF) and Mesenchymal Stem Cell Growth Medium DXF (MS) than in the control medium. SF and MS contain high fibroblast growth factor 2 (FGF2) concentrations, and we found upregulated FGF2 protein expression in cells cultured in SF or MS. Activation of the fibroblast growth factor receptor 1 (FGFR1)-mediated signaling pathway and stimulation of muscle satellite cell proliferation-related factors were confirmed by the presence of related biomarkers (FGFR1, FRS2, Raf1, ERK, p38, Pax7, and MyoD) as indicated by quantitative polymerase chain reaction, western blotting, and immunocytochemistry. Moreover, PD173074, an FGFR1 inhibitor suppressed cell proliferation in SF and MS and downregulated related biomarkers (FGFR1, FRS2, Raf1, and ERK). The promotion of cell proliferation in SF and MS was therefore attributed to FGF2, which indicates that FGFR1 activation in muscle satellite cells may be a target for improving the efficiency of cell-cultivated meat production.

FGF2 drives osteosarcoma metastasis through activating FGFR1-4 receptor pathway-mediated ICAM-1 expression

Osteosarcoma is a malignant tumor with high metastatic potential, such that the overall 5-year survival rate of patients with metastatic osteosarcoma is only 20%. Therefore, it is necessary to unravel the mechanisms of osteosarcoma metastasis to identify predictors of metastasis by which to develop new therapies. Fibroblast growth factor 2 (FGF2) is a growth factor involved in embryonic development, cell migration, and proliferation. The overexpression of FGF2 and FGF receptors (FGFRs) has been shown to enhance cancer cell proliferation in lung, breast, gastric, and prostate cancers as well as melanoma. Nonetheless, the roles of FGF2 and FGFRs in human osteosarcoma cells remain unknown. In the present study, we found that FGF2 was overexpressed in human osteosarcoma sections and correlated with lung metastasis. Treatment of FGF2 induced migration activity, invasion activity, and intercellular adhesion molecule (ICAM)-1 expression in osteosarcoma cells. In particular, the downregulation or antagonism of FGFR1-4 suppressed FGF2-induced ICAM-1 expression and cancer cell migration. Furthermore, FGFR1, FGFR2, FGFR3, and FGFR4 were involved in FGF2-induced the phospholipase Cβ/protein kinase Cα/proto-oncogene c-Src signaling pathway and triggered c-Jun nuclear translocation. Subsequent c-Jun upregulation of activator protein-1 transcription activity on the ICAM-1 promoter led to an increased migration of osteosarcoma cells. Moreover, the knockdown of endogenous FGF2 suppressed ICAM-1 expression and migration of osteosarcoma cells. These findings suggest that FGF2/FGFR1-4 signaling promotes metastasis via its direct downstream target gene ICAM-1, revealing a novel potential therapeutic target for osteosarcoma.

Bone health in children undergoing solid organ transplantation.

Pediatric solid organ transplant recipients are a unique and growing patient population who are at risk for metabolic bone disease both before and after transplantation. The odds of sustaining a fracture in adulthood are significantly higher if an individual has sustained at least one childhood fracture, therefore, close monitoring before and after transplant is essential. Emerging data in patients with chronic kidney disease mineral and bone disorder (CKD-MBD) and hepatic osteodystrophy highlights the role of fibroblast growth factor 23 in the pathogenesis of metabolic bone disease in these conditions. While dual X-ray absorptiometry (DXA) is the most widely used imaging modality for assessment of bone mass in children, quantitative computer tomography (QCT) is an emerging modality, especially for patients with glucocorticoid-induced osteoporosis. Solid organ transplantation improves organ function and quality of life; however, bone mineral density can decline following transplantation, particularly during the first three to six months. Immunosuppressive medications, including glucocorticoids, are a major contributing factor. Following transplant, treatment should be tailored to achieve mineral homeostasis, correct nutritional deficiencies, and improve physical conditioning. In summary, early identification and treatment of metabolic bone disease can improve the bone health status of pediatric transplant recipients as they enter adulthood. http://links.lww.com/MOP/A71.

FGF18 alleviates hepatic ischemia-reperfusion injury via the USP16-mediated KEAP1/Nrf2 signaling pathway in male mice

Hepatic ischemia-reperfusion injury (IRI) is a common complication occurs during hepatic resection and transplantation. However, the mechanisms underlying hepatic IRI have not been fully elucidated. Here, we aim to explore the role of fibroblast growth factor 18 (FGF18) in hepatic IRI. In this work, we find that Hepatic stellate cells (HSCs) secrete FGF18 and alleviates hepatocytes injury. HSCs-specific FGF18 deletion largely aggravates hepatic IRI. Mechanistically, FGF18 treatment reduces the levels of ubiquitin carboxyl-terminal hydrolase 16 (USP16), leading to increased ubiquitination levels of Kelch Like ECH Associated Protein 1 (KEAP1) and the activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Furthermore, USP16 interacts and deubiquitinates KEAP1. More importantly, Nrf2 directly binds to the promoter of USP16 and forms a negative feedback loop with USP16. Collectively, our results show FGF18 alleviates hepatic IRI by USP16/KEAP1/Nrf2 signaling pathway in male mice, suggesting that FGF18 represents a promising therapeutic approach for hepatic IRI.

Evaluation the role of fibroblast growth factors 23 and soluble transferrin receptor in pregnant women with iron deficiency anemia

Evaluation the role of fibroblast growth factors 23 and soluble transferrin receptor in pregnant women with iron deficiency anemia