ldn-193189 and Anemia

Anemia of chronic disease (ACD) or anemia of inflammation is prevalent in patients with chronic infection, autoimmune disease, cancer, and chronic kidney disease. ACD is associated with poor prognosis and lower quality of life. Management of ACD using intravenous iron and erythropoiesis stimulating agents are ineffective for some patients and are not without adverse effects, driving the need for new alternative therapies. Recent advances in our understanding of the molecular mechanisms of iron regulation reveal that increased hepcidin, the iron regulatory hormone, is a key factor in the development of ACD. In this review, we will summarize the role of hepcidin in iron homeostasis, its contribution to the pathophysiology of ACD, and novel strategies that modulate hepcidin and its target ferroportin for the treatment of ACD.

Topics: Anemia; Animals; Antibodies, Monoclonal; Antimicrobial Cationic Peptides; Bone Morphogenetic Protein 6; Cation Transport Proteins; Chronic Disease; Clinical Trials as Topic; Drug Evaluation, Preclinical; GPI-Linked Proteins; Hemochromatosis Protein; Hepcidins; Homeostasis; Humans; Inflammation; Interleukin-6; Iron; Mice; Molecular Targeted Therapy; Pyrazoles; Pyrimidines; RNA, Small Interfering; Signal Transduction; Smad Proteins; STAT3 Transcription Factor; Therapies, Investigational; Vitamin D

Topics: Administration, Oral; Anemia; Animals; Biological Availability; Blotting, Western; Bone Morphogenetic Protein Receptors, Type I; Bone Morphogenetic Proteins; Cells, Cultured; Female; Inflammation; Irritants; Mice; Mice, Inbred C57BL; Pyrazoles; Pyrimidines; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tissue Distribution; Turpentine

Anemia of chronic disease is a multifactorial disorder, resulting mainly from inflammation-driven reticuloendothelial iron retention, impaired erythropoiesis, and reduced biological activity of erythropoietin. Erythropoiesis-stimulating agents have been used for the treatment of anemia of chronic disease, although with varying response rates and potential adverse effects. Serum concentrations of hepcidin, a key regulator of iron homeostasis, are increased in patients with anemia of chronic disease and linked to the pathogenesis of this disease, because hepcidin blocks cellular iron egress, thus limiting availability of iron for erythropoiesis. We tested whether serum hepcidin levels can predict and affect the therapeutic efficacy of erythropoiesis-stimulating agent treatment using a well-established rat model of anemia of chronic disease. We found that high pre-treatment hepcidin levels correlated with an impaired hematologic response to an erythropoiesis-stimulating agent in rats with anemia of chronic disease. Combined treatment with an erythropoiesis-stimulating agent and an inhibitor of hepcidin expression, LDN-193189, significantly reduced serum hepcidin levels, mobilized iron from tissue stores, increased serum iron levels and improved hemoglobin levels more effectively than did the erythropoiesis-stimulating agent or LDN-193189 monotherapy. In parallel, both the erythropoiesis-stimulating agent and erythropoiesis-stimulating agent/LDN-193189 combined reduced the expression of cytokines known to inhibit erythropoiesis. We conclude that serum hepcidin levels can predict the hematologic responsiveness to erythropoiesis-stimulating agent therapy in anemia of chronic disease. Pharmacological inhibition of hepcidin formation improves the erythropoiesis-stimulating agent's therapeutic efficacy, which may favor a reduction of erythropoiesis-stimulating agent dosages, costs and side effects.

Topics: Anemia; Animals; Biomarkers; Chronic Disease; Drug Combinations; Drug Synergism; Erythropoiesis; Erythropoietin; Female; Gene Expression; Hematinics; Hepcidins; Humans; Interferon-gamma; Iron; Polysaccharides, Bacterial; Prognosis; Pyrazoles; Pyrimidines; Rats; Rats, Inbred Lew; RNA, Messenger; Tumor Necrosis Factor-alpha

Anemia of inflammation develops in settings of chronic inflammatory, infectious, or neoplastic disease. In this highly prevalent form of anemia, inflammatory cytokines, including IL-6, stimulate hepatic expression of hepcidin, which negatively regulates iron bioavailability by inactivating ferroportin. Hepcidin is transcriptionally regulated by IL-6 and bone morphogenetic protein (BMP) signaling. We hypothesized that inhibiting BMP signaling can reduce hepcidin expression and ameliorate hypoferremia and anemia associated with inflammation. In human hepatoma cells, IL-6-induced hepcidin expression, an effect that was inhibited by treatment with a BMP type I receptor inhibitor, LDN-193189, or BMP ligand antagonists noggin and ALK3-Fc. In zebrafish, the induction of hepcidin expression by transgenic expression of IL-6 was also reduced by LDN-193189. In mice, treatment with IL-6 or turpentine increased hepcidin expression and reduced serum iron, effects that were inhibited by LDN-193189 or ALK3-Fc. Chronic turpentine treatment led to microcytic anemia, which was prevented by concurrent administration of LDN-193189 or attenuated when LDN-193189 was administered after anemia was established. Our studies support the concept that BMP and IL-6 act together to regulate iron homeostasis and suggest that inhibition of BMP signaling may be an effective strategy for the treatment of anemia of inflammation.

Topics: Anemia; Animals; Antimicrobial Cationic Peptides; Bone Morphogenetic Protein Receptors, Type I; Bone Morphogenetic Proteins; Carrier Proteins; Hematopoietic Stem Cells; Hep G2 Cells; Hepcidins; Humans; Inflammation; Interleukin-6; Mice; Mice, Inbred C57BL; Pyrazoles; Pyrimidines; Recombinant Proteins; Signal Transduction; Turpentine; Zebrafish; Zebrafish Proteins

Anemia of chronic inflammation (ACI) is the most frequent anemia in hospitalized patients and is associated with significant morbidity. A major underlying mechanism of ACI is the retention of iron within cells of the reticuloendothelial system (RES), thus making the metal unavailable for efficient erythropoiesis. This reticuloendothelial iron sequestration is primarily mediated by excess levels of the iron regulatory peptide hepcidin down-regulating the functional expression of the only known cellular iron export protein ferroportin resulting in blockade of iron egress from these cells. Using a well-established rat model of ACI, we herein provide novel evidence for effective treatment of ACI by blocking endogenous hepcidin production using the small molecule dorsomorphin derivative LDN-193189 or the protein soluble hemojuvelin-Fc (HJV.Fc) to inhibit bone morphogenetic protein-Smad mediated signaling required for effective hepcidin transcription. Pharmacologic inhibition of hepcidin expression results in mobilization of iron from the RES, stimulation of erythropoiesis and correction of anemia. Thus, hepcidin lowering agents are a promising new class of pharmacologic drugs to effectively combat ACI.

Topics: Anemia; Animals; Antimicrobial Cationic Peptides; Cells, Cultured; Chronic Disease; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Gene Expression; GPI-Linked Proteins; Hemochromatosis Protein; Hepcidins; Immunoglobulin Fc Fragments; Inflammation; Membrane Proteins; Pyrazoles; Pyrimidines; Rats; Rats, Inbred Lew; Remission Induction