scholarly journals MO057HYPOXIA AS INDUCER OF FIBROBLAST GROWTH FACTOR 23 IN OSTEOCYTES

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Josephine Bonnemaijer ◽  
Pieter Koolwijk ◽  
Nathalie Bravenboer ◽  
Huib Van Essen ◽  
Marc Vervloet
Keyword(s):  
Cardiovascular Disease ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Hypoxia Inducible Factor ◽  
Left Ventricular ◽  
Fibroblast Growth ◽  
Normoxic Condition ◽  
Hypoxic Conditions ◽  
Human Sarcoma

Abstract Background and Aims Cardiovascular disease accounts for a major proportion of deaths among chronic kidney disease (CKD) patients. Fibroblast Growth Factor 23 (FGF23), a key regulator in phosphate homeostasis and mainly produced by osteocytes, is associated with CKD progression and cardiovascular mortality. FGF23 is involved in the development of left ventricular hypertrophy that can lead to congestive heart failure. Dysfunction of the heart causes tissue malperfusion, for instance in bones, inducing the hypoxia-inducible signaling pathway. Recently, the hypoxia-inducible factor-1α (HIF-1α) has been suggested as inducer of FGF23. Therefore, we investigated whether hypoxia in osteocytes induces FGF23 production mediated by the stabilization of HIFs. Method Human sarcoma osteogenic cells (SaOS2 cell line) and primary human osteocytes were cultured and exposed to hypoxic conditions (1% and 5% O2) and normoxic condition (20% O2) for 24 hours. qPCR was performed to investigate the expression of HIFs and FGF23 mRNA in these cells. HIFs protein expression was also evaluated by Western Blot analysis. Results Our data show that HIF-1α, and not HIF-2α, protein increases in SaOS2 cells and primary osteocytes under hypoxic conditions as compared to normoxic condition. In addition, we found that FGF23 mRNA expression is elevated in SaOS2 cells in these hypoxic conditions compared to normoxic condition (Fig.1). This increase was significant in SaOS2 cells exposed to 1% O2 (p <0.05). Preliminary data of primary osteocytes show that FGF23 mRNA is not expressed in hypoxic conditions compared with normoxic conditions (Fig.1). Conclusion HIF-1α protein was increased in both SaOS2 cells and primary osteocytes exposed to 1% O2. Hypoxic conditions upregulated FGF23 mRNA in SaOS2 cells. Taken together, these findings suggest that bone malperfusion upregulates FGF23 by stabilizing HIF-1α. This could then close a vicious circle where FGF23 induces cardiovascular disease, and circulatory failure upregulates FGF23.

scholarly journals Lipocalin 2 stimulates bone fibroblast growth factor 23 production in chronic kidney disease

Bone Research ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Guillaume Courbon ◽  
Connor Francis ◽  
Claire Gerber ◽  
Samantha Neuburg ◽  
Xueyan Wang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Growth Factor ◽  
Kidney Disease ◽  
Iron Deficiency ◽  
Fibroblast Growth Factor ◽  
Kidney Function ◽  
Fibroblast Growth Factor 23 ◽  
Left Ventricular ◽  
Fibroblast Growth ◽  
Lipocalin 2

AbstractBone-produced fibroblast growth factor 23 (FGF23) increases in response to inflammation and iron deficiency and contributes to cardiovascular mortality in chronic kidney disease (CKD). Neutrophil gelatinase-associated lipocalin (NGAL or lipocalin 2; LCN2 the murine homolog) is a pro-inflammatory and iron-shuttling molecule that is secreted in response to kidney injury and may promote CKD progression. We investigated bone FGF23 regulation by circulating LCN2. At 23 weeks, Col4a3KO mice showed impaired kidney function, increased levels of kidney and serum LCN2, increased bone and serum FGF23, anemia, and left ventricular hypertrophy (LVH). Deletion of Lcn2 in CKD mice did not improve kidney function or anemia but prevented the development of LVH and improved survival in association with marked reductions in serum FGF23. Lcn2 deletion specifically prevented FGF23 elevations in response to inflammation, but not iron deficiency or phosphate, and administration of LCN2 increased serum FGF23 in healthy and CKD mice by stimulating Fgf23 transcription via activation of cAMP-mediated signaling in bone cells. These results show that kidney-produced LCN2 is an important mediator of increased FGF23 production by bone in response to inflammation and in CKD. LCN2 inhibition might represent a potential therapeutic approach to lower FGF23 and improve outcomes in CKD.

scholarly journals Fibroblast Growth Factor 23 and Incident Cardiovascular Disease and Mortality in Middle‐Aged Adults

2021 ◽  
Author(s):  
Shejuti Paul ◽  
Mandy Wong ◽  
Ehimare Akhabue ◽  
Rupal C. Mehta ◽  
Holly Kramer ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiovascular Disease ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Hazard Ratio ◽  
Fibroblast Growth ◽  
Heart Failure Hospitalization ◽  
Middle Aged ◽  
Middle Aged Adults

Background Higher circulating fibroblast growth factor 23 (FGF23) associates with greater risk of cardiovascular disease (CVD) and mortality in older adults. The association of FGF23 with cardiovascular outcomes in younger populations has been incompletely explored. Methods and Results We measured C‐terminal FGF23 (cFGF23) and intact FGF23 (iFGF23) in 3151 middle‐aged adults (mean age, 45±4) who participated in the year 20 examination of the CARDIA (Coronary Artery Risk Development in Young Adults) study. We used separate Cox proportional hazards models to examine the associations of cFGF23 and iFGF23 with incident CVD and mortality, adjusting models sequentially for sociodemographic, clinical, and laboratory factors. A total of 157 incident CVD events and 135 deaths occurred over a median 7.6 years of follow‐up (interquartile range, 4.1–9.9). In fully adjusted models, there were no statistically significant associations of FGF23 with incident CVD events (hazard ratio per doubling of cFGF23: 1.14, 95%CI 0.97,1.34; iFGF23: 0.76, 95%CI 0.57,1.02) or all‐cause mortality (hazard ratio per doubling of cFGF23, 1.17; 95% CI, 1.00–1.38; iFGF23, 0.86; 95% CI, 0.64–1.17). In analyses stratified by CVD subtypes, higher cFGF23 was associated with greater risk of heart failure hospitalization (hazard ratio per doubling of cFGF23, 1.52; 95% CI, 1.18–1.96) but not coronary heart disease or stroke, whereas iFGF23 was not associated with CVD subtypes in any model. Conclusions In middle‐aged adults with few comorbidities, higher cFGF23 and iFGF23 were not independently associated with greater risk of CVD events or death. Higher cFGF23 was independently associated with greater risk of heart failure hospitalization.

Abstract P349: Association Of Fibroblast Growth Factor 23 With Incident Cardiovascular Disease And All-Cause Mortality In The Framingham Heart Study

Circulation ◽  
2014 ◽  
Vol 129 (suppl_1) ◽  
Author(s):  
Robin Haring ◽  
Ramachandran S Vasan ◽  
Henri Wallaschofski ◽  
Lisa Sullivan ◽  
Danielle Enserro
Keyword(s):  
Cardiovascular Disease ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Regression Models ◽  
Cox Regression ◽  
Fibroblast Growth Factor 23 ◽  
Positive Association ◽  
Fibroblast Growth ◽  
All Cause Mortality ◽  
Incident Cardiovascular Disease

Objective: To investigate the association of fibroblast growth factor 23 (FGF23) with incident cardiovascular disease (CVD) and mortality risk in the general population. Methods: We evaluated 3,236 Framingham Offspring and Omni Study participants to examine the associations of serum FGF23 (measured by immunoassay) with 10-year incident CVD (N = 2,823) and all-cause mortality (N = 3,223) using multivariable Cox regression models. Results: During a median follow-up time of 10.8 years (Q1, 10.0; Q3, 11.4), 347 participants developed new-onset CVD and 412 died. Age- and sex-adjusted Cox regression models revealed a positive association of FGF23 with incident CVD (hazard ratio (HR) per unit increase in logFGF23: 1.43, 95% confidence interval (CI) 1.11-1.84) and all-cause mortality (HR 2.26, 95% CI, 1.86-2.75). After multivariable adjustment, the association of FGF23 with incident CVD was rendered non-significant (HR 1.12, 95% CI 0.86-1.46), whereas the positive association of FGF23 with all-cause mortality was maintained (HR: 1.87, 95% CI: 1.52 - 2.29). Analyses modeling FGF23 quartiles yielded similar findings (multivariable-adjusted HR Q4 vs. Q1 for incident CVD: 1.17, 95% CI: 0.87 - 1.59; for death: 1.87, 95% CI: 1.38 - 2.53). Conclusion: In our large community-based sample, serum FGF23 shows an independent positive association with all-cause mortality, but not with incident CVD risk.

scholarly journals Fibroblast growth factor 23 (FGF23) level is associated with ultrafiltration rate in patients on hemodialysis

2020 ◽  
Author(s):  
Yoko Nishizawa ◽  
Yumi Hosoda ◽  
Ai Horimoto ◽  
Kiyotsugu Omae ◽  
Kyoko Ito ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Univariate Analysis ◽  
Hemodialysis Patients ◽  
Left Ventricular ◽  
Fibroblast Growth ◽  
Ultrafiltration Rate ◽  
Dialysis Duration ◽  
The Mean

Abstract Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that regulates renal phosphate reabsorption and vitamin D synthesis in renal proximal tubules. High circulating FGF23 levels are associated with increased mortality in patients with chronic kidney disease and those on dialysis. Current data also suggest higher circulating levels of FGF23 are associated with cardiovascular mortality, vascular calcification, and left ventricular hypertrophy; however, evidence on the role of FGF23 in patients on dialysis is incomplete, and some of the data, especially those on cardiovascular disease (CVD), are controversial. This study aimed to evaluate factors associated with FGF23 in hemodialysis patients with or without CVD. Randomly selected 76 patients on maintenance hemodialysis at a single hemodialysis center were enrolled. After the exclusion of eight patients with extremely outlying FGF23 levels, 68 patients, including 48 males and 46 patients with a CVD history, were included in the study. The mean age was 64.4 ± 12.1 years, and the mean dialysis duration was 12.7 ± 7.1 years. Dialysis duration, time-averaged concentration of urea (TAC-urea), ultrafiltration rate (UFR), blood pressure during hemodialysis session, laboratory data, and echocardiographic parameters including interventricular septum thickness (IVST), left ventricular mass indices (LVMI), and ejection fraction were included in univariate and multivariate analyses. The median lgFGF23 levels in the overall cohort and in those with and without CVD were 2.14 (interquartile range, IQR − 0.43 to − 4.23), 2.01 (− 0.52 to 4.12), and 2.59 (0.07 to 4.32), respectively, and there was no difference between the patients with and without CVD (p = 0.14). The univariate analysis revealed that FGF23 was significantly associated with age (r =  − 0.12, p < 0.01), duration of hemodialysis (r =  − 0.11, p < 0.01), TAC-urea (r = 0.29, p = 0.01), UFR (r = 0.26, p = 0.04), alkaline phosphatase (ALP; r =  − 0.27, p = 0.03), corrected serum calcium (cCa; r = 0.32, p < 0.01), serum phosphate (iP, r = 0.57, p < 0.01), intact parathyroid hormone (iPTH; r = 0.38, p < 0.01), IVST (r = 0.30, p = 0.01), and LVMI (r = 0.26, p = 0.04). In multivariate regression analysis, FGF23 was significantly associated with cCa (F = 25.6, p < 0.01), iP (F = 22.5, p < 0.01), iPTH (F = 19.2, p < 0.01), ALP (F = 5.34, p = 0.03), and UFR (F = 3.94, p = 0.05). In addition, the univariate analysis after the categorization of patients according to CVD indicated that FGF23 was significantly associated with cCa (r = 0.34, p = 0.02), iP (r = 0.41, p < 0.01), iPTH (r = 0.39, p = 0.01), and TAC-urea (r = 0.45, p < 0.01) in patients with CVD, whereas only IVST (r = 0.53, p = 0.04) was associated with FGF23 in those without CVD. FGF23 levels in hemodialysis patients were extremely high and associated not only with mineral bone disease-related factors but also with UFR. Additionally, dialysis efficacy might be associated with lower FGF23 levels in patients with CVD.

scholarly journals Fibroblast growth factor-23 is associated with imaging markers of diabetic cardiomyopathy and anti-diabetic therapeutics

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Martin H. Sørensen ◽  
Annemie S. Bojer ◽  
Niklas R. Jørgensen ◽  
David A. Broadbent ◽  
Sven Plein ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Kidney Function ◽  
Fibroblast Growth Factor 23 ◽  
Left Ventricular ◽  
Fibroblast Growth ◽  
Cardiovascular Morbidity And Mortality ◽  
Fgf 23

Abstract Background The biomarker fibroblast growth factor-23 (FGF-23) has been associated with increased cardiovascular morbidity and mortality in both patients with and without type 2 diabetes. The aim of this study was to evaluate the relationship between FGF-23 and cardiac structure, function and perfusion in patients with type 2 diabetes and normal or mildly impaired kidney function. Furthermore, to investigate the association between FGF-23, anti-diabetes therapy and the classic complications and risk factors associated with type 2 diabetes. Methods In this cross-sectional study, 246 patients with type 2 diabetes underwent echocardiography and advanced cardiac magnetic resonance imaging to assess left ventricular (LV) structure and function. In addition, myocardial blood flow (MBF) during rest and pharmacological stress (adenosine 140 µg/kg/min) were evaluated in 183 of the patients. Patients with eGFR < 60 ml/min/1.73 m2 were excluded. Results Median (Q1–Q3) FGF-23 was 74 (58–91) ng/L. Patients with FGF-23 above the median had lower MBF during stress (2.3 ± 0.9 vs. 2.7 ± 0.9 ml/min/g, P = 0.001) and lower overall myocardial perfusion reserve (MPR) (2.7 ± 0.8 vs. 3.3 ± 1.1, P < 0.001). LV mass (143 ± 40 vs. 138 ± 36 g, P = 0.04) and E/e* (8.5 ± 3.2 vs. 7.6 ± 2.7, P = 0.04) were higher in patients with FGF-23 above the median. In a linear model adjusted for age, sex, eGFR and hypertension, increasing FGF-23 was associated with decreased MPR (P < 0.01, R2 = 0.11) and increased E/e* (P < 0.01, R2 = 0.07). FGF-23 was lower in patients receiving glucagon like peptide-1 (GLP-1) analogues (71 (57–86) vs. 80 (60–98) ng/L, P = 0.01) than in those who did not receive GLP-1 analogues. Conclusions In patients with type 2 diabetes and normal or mildly impaired kidney function, increased levels of FGF-23 are associated with impaired cardiac diastolic function and decreased MPR, caused by a decrease in maximal MBF during stress. Use of GLP-1 analogues is associated with decreased levels of FGF-23. Clinical trial registrationhttps://www.clinicaltrials.gov. Unique identifier: NCT02684331. Date of registration: February 18, 2016

Fibroblast growth factor 23 and left ventricular hypertrophy in children on dialysis

2012 ◽  
Vol 27 (11) ◽  
pp. 2129-2136 ◽  
Author(s):  
Wacharee Seeherunvong ◽  
Carolyn L. Abitbol ◽  
Jayanthi Chandar ◽  
Paolo Rusconi ◽  
Gaston E. Zilleruelo ◽  
...  
Keyword(s):  
Growth Factor ◽  
Left Ventricular Hypertrophy ◽  
Fibroblast Growth Factor ◽  
Ventricular Hypertrophy ◽  
Fibroblast Growth Factor 23 ◽  
Left Ventricular ◽  
Fibroblast Growth
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