FGF23 promotes myocardial fibrosis in mice through activation of β-catenin

Hao, Huixin; Li, Xixian; Li, Qingman; Lin, Hairuo; Chen, Zhenhuan; Xie, Jin; Wang, Xuan; Liao, Wangjun; Bin, Jianping; Huang, Xiaobo; Kitakaze, Masafumi; Liao, Yulin

doi:10.18632/oncotarget.11623

Cited by 108 publications

(128 citation statements)

References 35 publications

(47 reference statements)

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“…In order to identify biomarkers of OSM activity we found that increased circulating FGF23 correlate with OSMR activation during the transition to HF [10,11]. Increased cardiac FGF23 levels have been also observed in experimental models of myocardial infarction [25,26], which is in agreement with our observation of strongly increased FGF23 expression in cardiomyocytes of the border zone in patients with CHD. Furthermore, we have previously demonstrated significantly higher levels of FGF23 in the pericardial fluid than in serum indicating a cardiac origin of this growth factor during heart failure [10].…”

Section: Discussionsupporting

confidence: 87%

“…From our viewpoint, there are three major reasons contributing to the complex biology of FGF23 regulation and function. First, there are additional sources of FGF23 besides the bone and cardiomyocytes such as non-cardiomyocytes [10], fibroblasts [26] and macrophages [35] indicating that at least in theory FGF23 might be released in significant amounts from any other organ under certain pathological conditions. Second, FGF23 can be secreted within hours in high amounts from cardiomyocytes as well as non-cardiomyocytes [10] while most cardiovascular studies focus on chronic events thus neglecting potential important immediate early functions in the heart.…”

Section: Discussionmentioning

confidence: 99%

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OSM-Stimulated Cardiomyocytes Release a C-Terminal Fragment of FGF23

Maringanti¹,

Kubin²,

Cetinkaya³

et al. 2017

J Cell Sci Ther

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Background: Recent studies emphasize a correlation of increased FGF23 with the pathogenesis of heart diseases. Although it is widely assumed that the bone and not the heart is the major source of FGF23 we previously demonstrated that oncostatin M (OSM) activated cardiomyocytes strongly secrete FGF23. This phosphatonin can be released as intact molecule (iFGF23) as well as C-terminal (cFGF23) and N-terminal (nFGF23) fragments. Since cleavage does not only inactivate iFGF23 but might also exert antagonizing activity we wanted to determine which form is secreted by cardiomyocytes. Methods: Adult cultured cardiomyocytes were stimulated with OSM or albumin as control. Supernatant and cell lysate were analyzed by Western blot (WB) and specific ELISAs against cFGF23 as well as iFGF23. Expression of FGF23 in cardiomyocytes of 6 patients with coronary heart diseases (CHD) was analyzed by confocal microscopy because OSM signaling cascades are activated after myocardial infarction. Results: WB analysis identified cFGF23 as well as nFGF23 while iFGF23 was hardly detectable in the supernatant of OSM-stimulated cardiomyocytes. Analysis of the supernatant by ELISAs revealed that less than 3% of this secreted phosphatonin was intact. In patients with CHD the number of FGF23 positive cardiomyocytes increased from 0.2% in the remote zone to 4.4% in the border zone. Conclusions: The expression and release of FGF23 by cardiomyocytes indicate local as well as systemic functions. The determination of the ratio of iFGF23/cFGF23 will be essential to understand the functional role of this growth factor in patients with cardiac diseases.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

OSM-Stimulated Cardiomyocytes Release a C-Terminal Fragment of FGF23

Maringanti¹,

Kubin²,

Cetinkaya³

et al. 2017

J Cell Sci Ther

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“…Surprisingly, the opposite effect was seen for Fgf2 in this study, suggesting that Fgf16 antagonizes a pro-fibrotic function of Fgf2. A pro-fibrotic effect in the heart was also demonstrated for Fgf23, which is upregulated in the heart and the bone after myocardial infarction and promotes myocardial fibrosis and exacerbates diastolic dysfunction in response to infarction or ischemia reperfusion injury (Hao et al, 2016). Taken together, it seems that the effect of FGFs on cardiac fibrosis depends on the type of FGF, the target cell affected, and potentially also the injury model.…”

Section: Fgf Signaling In the Repair Of Cardiac And Skeletal Muscle Fmentioning

confidence: 87%

Fibroblast growth factors: key players in regeneration and tissue repair

2017

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Tissue injury initiates a complex repair process, which in some organisms can lead to the complete regeneration of a tissue. In mammals, however, the repair of most organs is imperfect and results in scar formation. Both regeneration and repair are orchestrated by a highly coordinated interplay of different growth factors and cytokines. Among the key players are the fibroblast growth factors (FGFs), which control the migration, proliferation, differentiation and survival of different cell types. In addition, FGFs influence the expression of other factors involved in the regenerative response. Here, we summarize current knowledge on the roles of endogenous FGFs in regeneration and repair in different organisms and in different tissues and organs. Gaining a better understanding of these FGF activities is important for appropriate modulation of FGF signaling after injury to prevent impaired healing and to promote organ regeneration in humans.

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“…GDF15 regulates inflammation and apoptosis, both key mechanisms in cardiac remodelling that are potentially associated with incident HF 48,49 . FGF23 is released by the osteocytes and is essential for the regulation of the metabolism of phosphate, calcium and vitamin D. Importantly, FGF23 promotes myocardial fibrosis and has been associated with coronary heart disease and HF 50,51 .…”

Section: Extracellular Matrix Remodelling Angiogenesis and Growth CLmentioning

confidence: 99%

Proteomic Bioprofiles and Mechanistic Pathways of Progression to Heart Failure

Ferreira

Verdonschot

Collier

et al. 2019

Circ: Heart Failure

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Background: Identifying the mechanistic pathways potentially associated with incident HF may provide a basis for novel preventive strategies. Methods and Results:To identify proteomic biomarkers and the potential underlying mechanistic pathways that may be associated with incident HF defined as first hospitalization for HF, a nestedmatched case-control design was used with cases (incident HF) and controls (without HF) selected from 3 cohorts (>20,000 individuals). Controls were matched on cohort, follow-up time, age, and sex.Two independent sample sets (a "discovery" set, with 286 cases and 591 controls and a "replication" set with 276 cases and 280 controls) were used to discover and replicate the findings. 252 circulating proteins in the plasma were studied. Adjusting for the matching variables age, sex, and follow-up time (and correcting for multiplicity of tests), 89 proteins were found to be associated with incident HF in the discovery phase, of which 38 were also associated with incident HF in the replication phase.These 38 proteins pointed to 4 main network clusters underlying incident HF: 1) inflammation and apoptosis, indicated by the expression of the TNF-family members; 2) extracellular matrix remodelling, angiogenesis and growth, indicated by the expression of proteins associated with collagen metabolism, endothelial function and vascular homeostasis; 3) blood pressure regulation, indicated by the expression of natriuretic peptides and proteins related to the renin angiotensin aldosterone system; and 4) metabolism, associated with cholesterol and atherosclerosis.Conclusion: Clusters of biomarkers associated with mechanistic pathways leading to HF were identified linking inflammation, apoptosis, vascular function, matrix remodelling, blood pressure control and metabolism. These findings provide important insight on the pathophysiological mechanisms leading to HF.

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FGF23 promotes myocardial fibrosis in mice through activation of β-catenin

Cited by 108 publications

References 35 publications

OSM-Stimulated Cardiomyocytes Release a C-Terminal Fragment of FGF23

OSM-Stimulated Cardiomyocytes Release a C-Terminal Fragment of FGF23

Fibroblast growth factors: key players in regeneration and tissue repair

Proteomic Bioprofiles and Mechanistic Pathways of Progression to Heart Failure

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