The mechanism of action of erythropoietin

Abstract

The proliferation and differentiation of committed erythroid progenitor cells is regulated by the glycoprotein hormone erythropoietin. Erythropoietin increases the number of developing erythroid precursors and accelerates the release of reticulocytes from the marrow without markedly altering the cell cycle length or number of mitotic divisions involved in the differentiation process. Although the hormone has been purified, molecularly cloned and sequenced, its secondary and tertiary structure and active site have not been defined. Erythropoietin has both mitogenic and differentiation functions, and whether an erythroid progenitor cell responds to the hormone by proliferating or differentiating appears to depend on its level of maturation. Erythroid progenitor cells are responsive to a variety of growth and developmental agents but only erythropoietin appears obligatory in vivo for terminal differentiation. Erythropoietin interacts with its target cells through specific high-affinity receptors and Ca*+ may be involved in the receptor-ligand interaction. Caz+ may also be involved in the induction of differentiation by erythropoietin. An increase in RNA synthesis due to activation of transcription is one of the earliest recognized effects of the hormone and appears not to require protein or DNA synthesis but the initial sequence of biochemical events triggered by erythropoietin is still undefined.are not freely accessible in the native state. Given the limited studies to date on the hormone's physical and chemical properties, it is clear that much remains to be learned about the erythropoietin molecule, particularly with respect to its structure and active site. With the availability of abundant quantities of hormone, substantial progress in this area can now be expected. m e Physiology of ErythropoiesisThe principal function of the red cell is to transport oxygen from the lungs to the tissues, and tissue oxygen demands are linked to red cell production through the action of erythropoietin. By unknown mechanisms, hypoxia stimulates erythropoietin production while a surfeit of oxygen suppresses it. Although fluctuations thus occur in the plasma erythropoietin concentration, it is worth emphasizing that such fluctuations are usually temporary and that production of the hormone is not an intermittent process. For example, while hypoxia evokes an increase in the plasma erythropoietin concentration, this soon subsides to normal even if the hypoxia persists [18, 191. Furthermore, erythrocytosis, either endogenous as in polycythemia Vera or induced by hypertransfusion, does not entirely suppress erythropoietin production [20], a phenomenon not recognized before the development of a sensitive radioimmunoassay for the hormone.Whole animal studies indicate that erythropoietin increases the number of developing erythroid precursors and accelerates the release of reticulocytes from the marrow without markedly altering the cell-cycle length or the number of mitotic divisions involved in the differentiation process [21]. In addit...

Serial immunoreactive erythropoietin levels in autologous blood donors

“…30 The rate of recovery from red cell loss depends on the degree of stimulation of erythropoiesis, of which EPO is considered to be the main regulator. 11 Our results in the patients studied show that acute reduction of the blood volume by 450 mL caused a biphasic increase of plasma EPO levels. A peak concentration was measured 24 hours after donation, which preceded the lowest hemoglobin concentration.…”

“…11 As the increase in EPO concentration and the stimulation of erythropoiesis are only moderate following repeated phlebotomy, different strategies may be adopted to increase EPO levels and erythropoiesis.…”

“…11 Increasing the availability of EPO may therefore enhance the efficiency of preoperative donation programs. This increased availability of EPO may be achieved by allowing the modulation of donation schemes (shorter donation intervals, lower minimum predonation hematocrits) to enhance endogenous EPO formation.…”

Serum immunoreactive erythropoietin of children in health and disease

“…Erythropoietin (EPO) is considered the primary regulator of red cell formation [20]. The development of sensitive radioimmunoassays for the estimation of EPO allows the routine measurement of the hormone in biological fluids.…”

Age-Related Differences in Erythropoietic Response to Recombinant Human Erythropoietin: Comparison in Adult and Infant Rhesus Monkeys

“…Affected babies may need transfusions because of clinical signs associated with impaired peripheral oxygen delivery (2). Inadequate production of EPO, the primary regulatory hormone for erythropoiesis (3), is thought to contribute to anemia of prematurity. Affected infants have low circulating levels of EPO (4-7) and normal numbers of peripheral blood erythroid burst forming units (8) and bone marrow colony forming units (9).…”