Erythropoietin: biology and clinical use

Red cell production in vertebrates is controlled by a glycoprotein hormone known as erythropoietin (Ep), which is produced by the kidney in response to hypoxia and acts on the marrow to selectively stimulate erythropoiesis. The gene for Ep has recently been cloned, and highly pure recombinant human Ep (rHuEp) is now available in considerable quantity. This has led to a better understanding of many aspects of Ep biology and to clinical trials in humans. The amino acid sequence of Ep is now completely known, and the protein portion of the natural hormone and the recombinant product are identical. Both the natural hormone and rHuEp produced in Chinese hamster ovary cells are heavily glycosylated in a very similar manner. This glycosylation is not necessary for in vitro activity but is required for activity in vivo. Radioimmunoassays (RIAs), which use labeled rHuEp, have been developed and are sufficiently sensitive to measure normal plasma levels. However, since Ep exists in plasma in several forms that vary in their immunologic and biologic activities, the ability of a RIA to provide information on the pathogenesis of clinical disease may be limited and should be referenced to the polycythemic mouse assay. The kidney's role in the production of Ep has been greatly clarified. Studies using probes to Ep mRNA have shown that Ep is primarily made in the kidney and secreted as the intact hormone. Moreover, renal secretion appears to be regulated by the rate of synthesis of the hormone, which in turn is dependent on the rate of synthesis of Ep mRNA. The cells that produce Ep have been identified as peritubular interstitial cells that may be endothelial in origin. The initiating mechanism for hormone production appears primarily to involve recruitment of additional cells rather than increased production by individual cells. Ep primarily acts on the marrow to stimulate the growth and maturation of early cells in the erythroid lineage that are known as the burst-forming unit-erythroid (BFU-E) and colony-forming unit-erythroid (CFU-E). The BFU-E is a very early cell closely related to the pluripotent stem cell, while the CFU-E is a later cell close to the first recognizable erythroblast.(ABSTRACT TRUNCATED AT 400 WORDS)