Erythropoietin in bone homeostasis—Implications for efficacious anemia therapy. (21st January 2021)

• Record Type: Journal Article
• Authors: Lappin, Katrina M.; Mills, Ken I.; Lappin, Terence R.
• Is Part Of: Stem cells translational medicine. Volume 10:Number 6(2021)
• Page Start: 836
• Page End: 843
• Publication Date: 2021-01-21
• Subjects: bone -- erythropoietin -- hematopoiesis -- osteoblast; Stem cells -- Periodicals; Regenerative medicine -- Periodicals; Periodicals; 616.0277405
• DOI: 10.1002/sctm.20-0387
• Languages: English
• ISSNs: 2157-6564

Abstract

Abstract: Bone homeostasis and hematopoiesis are irrevocably linked in the hypoxic environment of the bone marrow. Erythropoietin (Epo) regulates erythropoiesis by binding to its receptor, Epor, on erythroid progenitor cells. The continuous process of bone remodeling is achieved by the finely balanced activity of osteoblasts in bone synthesis and osteoclasts in bone resorption. Both osteoblasts and osteoclasts express functional Epors, but the underlying mechanism of Epo-Epor signaling in bone homeostasis is incompletely understood. Two recent publications have provided new insights into the contribution of endogenous Epo to bone homeostasis. Suresh et al examined Epo-Epor signaling in osteoblasts in bone formation in mice and Deshet-Unger et al investigated osteoclastogenesis arising from transdifferentiation of B cells. Both groups also studied bone loss in mice caused by exogenous human recombinant EPO-stimulated erythropoiesis. They found that either deletion of Epor in osteoblasts or conditional knockdown of Epor in B cells attenuates EPO-driven bone loss. These findings have direct clinical implications because patients on long-term treatment for anemia may have an increased risk of bone fractures. Phase 3 trials of small molecule inhibitors of the PHD enzymes (hypoxia inducible factor-prolyl hydroxylase inhibitors [HIF-PHIs]), such as Roxadustat, have shown improved iron metabolism and increased circulating Epo levels in a titratable manner, avoiding the supraphysiologic increases that often accompany intravenous EPO therapy. The new evidence presented by Suresh and Deshet-Unger and their colleagues on the effects of EPO-stimulated erythropoiesis on bone homeostasis seems likely to stimulate discussion on the relative merits and safety of EPO and HIF-PHIs. Abstract : The HIF-PHD-Epo axis is activated by prolyl hydroxylase inhibitors. Schematic representation of the oxygen-sensing mechanism that regulates transcription of genes containing a hypoxia response element (HRE). In the presence of oxygen, PHD site-specifically hydroxylates HIF-α, targeting it for degradation by VHL. In the absence of oxygen HIF-1α dimerizes with its stable partner HIF-1β in the nucleus (also known as ARNT) to facilitate a complex array of gene transcriptional responses to hypoxia through its three isoforms (HIF-1α, HIF-2α, and HIF-3α). The three prolyl hydroxylase paralogues, PHD1, PHD2 and PHD3 are dioxygenases, which utilize molecular oxygen (O2 ) and 2-oxoglutarate (2-OG) for HIF-α hydroxylation. PHD2 is the principal regulator of HIF activity in most cells. In the case of erythropoietin, PHD2 hydroxylates HIF-2α, whereas glycolytic genes such as PGK are HIF-1α-driven. Early HIF-PHIs (hypoxia-inducible factor prolyl hydroxylase inhibitors), such as Roxadustat, were designed to incorporate a side chain structurally analogous to 2-OG.