Endothelial Oxygen Sensing in Alveolar Maintenance

Hodson, Emma J.; Ratcliffe, Peter J.

doi:10.1164/rccm.202006-2149ed

Cited by 2 publications

(1 citation statement)

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“…It will be of interest to learn whether some of these small molecules that specifically enhance HIF‐2α function can replace recombinant EPO in the long‐term treatment of anemia. Furthermore, some of the novel small molecules and the clinically approved HIF‐PHDs may find clinical application in the treatment of disorders such as vascular insufficiency and airway degeneration 63,64 …”

Section: Clinical Insights Of Epo‐epor Signalingmentioning

confidence: 99%

Erythropoietin in bone homeostasis—Implications for efficacious anemia therapy

Lappin

Mills

Lappin

2021

Stem Cells Translational Medicine

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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. | INTRODUCTIONBone homeostasis is a highly organized process that requires the activity of multiple cells to coordinate bone formation and resorption.Osteoblasts, derived from mesenchymal stem cells, are responsible for bone matrix synthesis and mineralization, whereas osteoclasts derived from myeloid progenitor cells, are responsible for bone resorption. This continuous remodeling is finely balanced and is maintained by the combined action of growth factors and cytokines in the hypoxic bone marrow environment, and systemic factors such as calcitonin and estrogens. 1,2 During embryogenesis blood precursors migrate and colonize spaces created in the primitive bone marrow. 3 This close physical association provides the basis for the coordination between bone homeostasis and erythropoiesis in the bone marrow cavity that is maintained throughout adult life. The bone marrow produces

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Section: Clinical Insights Of Epo‐epor Signalingmentioning

confidence: 99%