Control of Erythropoiesis by FGF23 and Pit1 – CERF

Bone cells secrete multiple factors and hormones under physiological and pathological conditions. New functions or properties of these factors are progressively unravelled. In adults, osteoblasts, responsible for osteogenesis, and hematopoietic cells, responsible for hematopoiesis, are closely associated in the bone marrow, suggesting a reciprocal relationship between the two. On the basis of observation made in patients and of data obtained in our laboratory (work performed in collaboration between group1 and group 2) the aim of this project is to explore new ways of crosstalk between bone cells and hematopoietic cells involving a recently identified hormone synthesized by bone cells, Fibroblast growth factor 23 (FGF23), which control phosphate homeostasis. FGF23 induces renal phosphate excretion and decreases bone mineralization. Following patients with sickle cell disease we have observed that the plasma concentration of FGF23 was markedly increased and correlated with the severity of anaemia. We found a similar association between haemoglobin concentration and FGF23 level in subjects who had no haemoglobin disorders. None of the factors known to influence FGF23 production (serum phosphate or calcitriol concentration, altered renal function) were modified in these subjects.
We have recently demonstrated that a phosphate transporter, Pit1, whose expression is potentially down regulated by FGF23, plays a central role in red blood cell progenitor maturation. Pit1 is expressed in different cell types including bone cells and hematopoietic progenitor. Beside its ability to transport phosphate, data recently published by our group showed that Pit1 controls cell proliferation, cell differentiation and apoptosis. Our group invalidated the expression of Pit1 in mice. The phenotype of these mice is early lethal in utero at around 12 days. We demonstrated that the death of the embryo was due to a defect of erythroid maturation. We showed that Pit1 expression in the erythroid precursors is under the control of the transcription factor EKLF, which is mandatory for erythroid maturation. Partial deletion of Pit1 gene in the hematopoietic cells in adult mice impairs red blood cell maturation.
From these observations obtained in patients and in mice we shall determine if FGF23 can interfere with red blood cell production and if this effect involves the modification of Pit1 activity or expression. We will also investigate the role of haemoglobin levels or erythropoietin as factors potentially controlling FGF23 production. FGF23 could control red blood cells maturation and may be a factor allowing the coupling of hematopoiesis with bone function. This new loop of regulation may play an important role in the genesis of anaemia in patients with renal insufficiency. Indeed, decline in renal function is associated with a marked increased in plasma FGF23 concentration, anaemia and a resistance to erythropoietin action. FGF23 may alter red blood cell production by decreasing Pit1 expression and activity, which may participate to the resistance to erythropoietin action. The results of this study may allow the development of new treatment of anaemia in renal insufficiency.
This project will involve two groups:
Group 1 (PI’s group, INSERM U845) has an internationally recognized expertise in the research field of phosphate and bone homeostasis and phosphate transporters. The results obtained in the domain were funded by ANR (PHYSIOPATH ANR-07-PHYSIO-017-01; and ANR PIT LIRIC).
Group 2 has a recognized expertise in the field of hematology (Université Paris Descartes Laboratoire d’Excellence (LABEX) GR-Ex).
Collaboration between the two groups has already led to a common publication.