Transforming Growth-factor-β is a Potent Inhibitor of FGF23 Secretion from Oncostatin M Stimulated Cardiomyocytes

Objectives: Fibroblast growth factor 23 (FGF23) became recently recognized as a heart failure (HF) marker. We found increased cardiac transcript and protein levels of this phosphatonin in patients with myocarditis, aortic stenosis, ischemic and dilated cardiomyopathy. We demonstrated previously that oncostatin M (OSM) massively induces the secretion of FGF23 by cardiomyocytes during the course of HF. Since OSM is an inflammatory cytokine we questioned whether anti-inflammatory signaling could downregulate the release of FGF23 by cardiomyocytes.

Methods: To investigate the inhibitory effect of anti-inflammatory signaling on the secretion of FGF23 we co-treated cultures of adult cardiomyocytes with interleukin-4, 10, 13 and transforming growth factor-β (TGF-β). The expression and secretion of FGF23 in OSM treated cultures were monitored by ELISA, RT-PCR, confocal microscopy (CM) and Western blots (WB). To determine the relationship of anti-inflammatory cytokines and the expression of FGF23 after myocardial infarction we used a mouse model of LAD ligation. This cardiac mouse tissue was analyzed by CM.

Results: We did not see any inhibition of Il-4, Il-10 and Il-13 on the expression of FGF23 in cardiomyocyte cultures. However, the massive increase of FGF23 as determined by ELISA in the supernatant of OSM treated cultures was strongly reduced 36h after TGF-β co-treatment (710 ± 45pg/ml in OSM cultures (n = 4) vs 2 ± 0.5pg/ml in controls (p< 0.01, n = 4) or versus 181 ± 10pg/ml in OSM plusTGF-β cultures (p< 0.04, n = 4). These observations were confirmed by RT-PCR and WB. Analysis of the infarcted area showed little expression of Il-4, Il-10 and Il-13. However, there was significant expression of TGF-β in cardiomyocytes at the remote zone but little expression of FGF23 was observed. Importantly, there was a large number of OSM releasing macrophages and significant numbers of FGF23 positive cardiomyocytes in the border zone.

Conclusions: We conclude that TGF-β - but not Il-4, Il-10 and Il-13 - restricts FGF23 expression to the infarct area by inhibiting OSM signaling in the remote zone. Our data indicate that the TGF-β/OSM/FGF23 system exerts a yet to defined complex function after myocardial infarction probably by directing FGF23 activity into the border zone.