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

Abstract

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.

The Role of Oncostatin M and Its Receptor Complexes in Cardiomyocyte Protection, Regeneration, and Failure

“…To distinguish an OSMRmediated effect from other IL-6 receptor complexes, one must look for more specific effects of this cytokine. ANP and BNP are regarded as biomarkers for cardiac remodeling induced by various cardioactive agents including FGF2, but only the increasingly recognized cardiac remodeling marker FGF-23 appears to be specific to cardiac OSM activity [11,17,[138][139][140]. Other strong indicators of fetal remodeling are non-muscle α-actinins (Actn1 and Actn4), which are expressed during the early postnatal weeks in the normal human myocardium but are barely detectable in adult cardiomyocytes [116].…”