>• Uroporphyrinogen translation of RNAs involved in iron storage, iron transport and haem synthesis (see Chapter 3). The recent discovery of hepcidin, which controls the uptake of iron from the gut, iron transport across the placenta and iron release from macrophages, adds another level of control to this complex system (see Chapter 3). Not surprisingly, diseases affecting the supply of iron (iron deficiency and the anaemia of chronic disease), the synthesis of haem (sideroblastic anaemia, lead poisoning, alcohol ingestion) or the synthesis of globin (thalassaemia) have inter-related effects on globin synthesis, haem synthesis and iron metabolism (Figure 2.5).
No mechanistic connection between haemoglobin synthesis and erythroid proliferation or differentiation has yet been established. However, it has been postulated that haemoglobin content and/or haemoglobin concentration per se may be a negative regulator of cell division. When haemoglobin synthesis is reduced or delayed, as in iron deficiency, the cells may undergo an extra division, yielding smaller hypochromic cells. Alternatively, when haemoglobin synthesis exceeds DNA synthesis, as in megaloblastic anaemias, the cells may skip a division and nuclear extrusion may occur early, resulting in macrocy-tosis. Although plausible, these hypotheses remain unproven.
The normal red cell lifespan is 120 days and therefore, to maintain equilibrium, approximately 1% of the circulating red cell pool must be replaced daily. For a total of ~3 X 1013 circulating erythrocytes and a lifespan of 120 days, the erythrocyte production rate needs to be maintained at ~1010/h in the steady state.
Erythropoiesis accounts for about 20% of the nucleated cells in a normal bone marrow reflected in the myeloid-erythroid ratio (usually ~4:1). As committed erythroid cells become late BFU-E and CFU-E, they upregulate expression of the receptor for erythropoietin (EpoR). Signalling through this receptor is thought to prevent apoptosis and may also stimulate proliferation. Therefore, at the late BFU-E and CFU-E stages there is considerable potential for controlling the overall level of erythropoiesis. Soon after reaching the CFU-E stage, erythroid cells enter the phase of terminal differentiation, after which there is only limited potential for further expansion. The two major components regulating erythropoiesis include sensing hypoxia and regulating the supply of erythroid precursors, mainly by controlling the numbers of erythroid progenitors via the Epo-EpoR signalling pathway.
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