Cystathionine β-Synthase (CBS) Deficiency Suppressed Erythropoiesis by Disrupting Iron Supply to Erythroid Progenitors

Background: We recently demonstrated that the reduced iron usage due to suppressed erythropoiesis is a major cause of the systemic iron overload in CBS knockout (CBS-/-) mice. However, the molecular mechanisms by which CBS deficiency suppresses erythropoiesis are unknown. Methods: Here, we therefore examined the changes in the ratio of granulocyte/erythroid cells, iron content, the expression of erythropoietin (EPO), iron-metabolism proteins including transferrin receptor 1 (TfR1), ferroportin 1 (Fpn1) and iron regulatory proteins (IRPs), and other molecules that affect iron-metabolism, including hypoxia inducible factor-2 subunit α (HIF-2α), nuclear factor erythroid 2-related factor-2 (Nrf2), and Kelch-like ECH-associated protein 1 (Keap1) in the blood, bone marrow, bone marrow-derived macrophages, liver or spleen of CBS-/- (homozygous), CBS+/- (heterozygous) and CBS+/+ (Wild Type) mice. Findings & Interpretation: Our findings demonstrated that CBS deficiency suppressed erythropoiesis by disrupting iron supply mainly via EPO/IRP/TfR1, Hepcidin/Fpn1, HIF-2α/EPO/Fpn1 and Keap1/Nrf2/Fpn1 pathways in macrophage or erythroid progenitors of rats. Funding: Supported by the National Natural Science Foundation of China (NSFC31571195), and the Competitive Earmarked Grants of the Hong Kong Research Grants Council (GRF14111815, GRF 14167817, GRF14107616). Declaration of Interest: The authors have no financial or competing interests to disclose. Ethical Approval: All animal care and experimental protocols were performed according to the Animal Management Rules of the Ministry of Health of China, and approved by the Animal Ethics Committees of Fudan University (NDFC31271132) and The Chinese University of Hong Kong (GRF14111815).