Therapeutic Target for β-Thalassemia Patients

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This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10010189

Iron homeostasis is regulated by hepcidin, a hepatic hormone that controls dietary iron absorption and plasma iron concentration. Hepcidin binds to the only known iron export protein, ferroportin (FPN), which regulates its expression. The major factors that implicate hepcidin regulation include iron stores, hypoxia, inflammation, and erythropoiesis. When erythropoietic activity is suppressed, hepcidin expression is hampered, leading to deficiency, thus causing an iron overload in iron-loading anemia, such as β-thalassemia. Iron overload is the principal cause of mortality and morbidity in β-thalassemia patients with or without blood transfusion dependence. In the case of thalassemia major, the primary cause of iron overload is blood transfusion. In contrast, iron overload is attributed to hepcidin deficiency and hyperabsorption of dietary iron in non-transfusion thalassemia. Beta-thalassemia patients showed marked hepcidin suppression, anemia, iron overload, and ineffective erythropoiesis (IE). Recent molecular research has prompted the discovery of new diagnostic markers and therapeutic targets for several diseases, including β-thalassemia.

hepcidin HbE/β-thalassemia iron overload ferroportin iron homeostasis signaling pathways

1. Thalassemia Syndrome

Thalassemia is an inherited autosomal recessive blood disorder that can be divided into either alpha (α) or beta (β) depending on the affected α or β globin chain ^[1]. The adult hemoglobin (HbA) consists of two α and two β (α2β2) chains in each HbA molecule ^[2]^[3]. Alpha-thalassemia occurs if one or more of the four alleles that code for α globin is missing or damaged ^[4]. On the other hand, β-thalassemia is caused by mutation in the β globin gene leading to a reduction in β globin or production of abnormal hemoglobin.

2. Beta-Thalassemia

Notably, β-thalassemia is highly reported in the Mediterranean and Southeast Asian countries as one of the most common genetic disorders ^[5]. Nevertheless, a lack of information on knowledge, attitudes, and practices towards β-thalassemia poses a challenge in many countries, including Malaysia ^[5]. This disease can be categorized into β-thalassemia major, intermedia, or minor ^[6]. β-thalassemia major and intermedia are genetically homozygous or heterozygous (β⁰ and β⁺), whereas β-thalassemia minor is usually heterozygous ^[6].

The β globin chain is encoded by the β globin gene (HBB), located on chromosome 11 at the short arm position 15.4 ^[7]^[8]. Individuals with β-thalassemia major and intermedia inherit the mutation in both copies of the HBB gene, affecting normal β globin chain production ^[7]. The clinical features of β-thalassemia major are revealed as early as the first two years of the patient’s life and are usually connected to transfusional iron overload, whereas the clinical presentation for β-thalassemia intermedia occurs later in life ^[2]. In contrast, β-thalassemia minor or trait has one mutation in the HBB gene and is described as a carrier ^[6]. They are usually symptomless, with a hypochromic microcytic blood picture and mild anemia, and can potentially increase in severity with malnutrition ^[6].

Beta-thalassemia can be present alongside other diseases associated with an abnormal β globin chain, such as the hemoglobin E (HbE) disease, exhibiting severe anemia ^[2]. HbE is a hemoglobin (Hb) variant caused by a single base substitution of glutamic acid to lysine at position 26 of the globin chain, commonly found in Southeast Asia ^[9]. It can be classified into three types: heterozygous, homozygous, or compound heterozygous ^[9]. When the HbE trait is coinherited with β-thalassemia, it is called compound heterozygous, a condition known as HbE/β-thalassemia, which resembles homozygous β⁰-thalassemia clinically and hematologically ^[10].

The phenotypic heterogeneity of HbE/β-thalassemia can range from mild asymptomatic anemia to a severe form that requires regular blood transfusion ^[11]. A study in Sri Lanka revealed that the HbE/β-thalassemia phenotype is unstable during the first 10 years of life but gradually stabilizes as the patient gets older ^[11]. This condition is caused by various changes in anemia and erythroid expansion progression during their early life ^[11]. However, the lack of knowledge on the classification of the disease severity will affect the understanding of HbE/β-thalassemia clinical progression with age ^[11].

2. Hepcidin Expression in β-Thalassemia

Hepcidin expression in thalassemia was first reported in a mouse model of severe anemia (C57BI/6 Hbbth3/+) ^[12]. Furthermore, a decline in serum hepcidin levels has been reported in HbE/β-thalassemia patients, β-thalassemia trait, and HbE trait carriers ^[13]. The decreased serum hepcidin levels in β-thalassemia patients are associated with the downregulation of hepcidin expression in liver cells, resulting in continuous absorption of dietary iron that leads to iron overload ^[14]. In individuals with thalassemia major and intermedia, liver hepcidin mRNA expression is inversely associated with soluble transferrin receptor (sTfR) and erythropoietin (EPO), but not with iron storage ^[15]. Suppression of hepcidin in HbE/β-thalassemia patients is linked to increased iron loading, saturated iron-binding proteins, and organ damage ^[13]. Moreover, hepcidin suppression with enhanced iron absorption was found in the β-thalassemia trait ^[16].

2.1. Hepcidin Regulation in β-Thalassemia

Hepcidin is suppressed in β-thalassemia patients with increasing iron absorption in response to the iron demand by erythroblasts due to tissue hypoxia erythropoietin (EPO) production and anemia ^[17]. During the differentiation process, several hepcidin inhibitors are released from erythroblasts to regulate hepcidin expression in β-thalassemia. Growth differentiation factor 15 (GDF15) serum level is inversely correlated with hepcidin expression in hepatocytes of thalassemia patients ^[18]. Meanwhile, twisted-gastrulation 1 (TWSG1) was upregulated in the bone marrow, spleen, and liver of mice with β-thalassemia major and intermedia, associated with hepcidin suppression and absence of bone morphogenetic protein (BMP). Additionally, human hepatocytes’ TWSG1 indirectly suppressed hepcidin expression through inhibition of BMP-mediated signaling ^[19].

Erythroferrone (ERFE) hormone functions as a negative regulator of hepcidin synthesis. Elevated ERFE expression is associated with increased erythropoietin and hepcidin suppression in mice models with thalassemia intermediate during stress erythropoiesis. The ERFE-deficient mice failed to suppress hepcidin after hemorrhage and erythropoietin administration ^[20]. Therefore, increased iron absorption in β-thalassemia is most likely attributed to increased ERFE expression and other hypoxia-related molecules that suppress hepcidin synthesis or increase ferroportin (FPN) expression ^[21]^[22].

2.2. Regulatory Effect of Hepcidin Transcription

Hepcidin is regulated by various stimuli, such as inflammation, plasma iron, anemia, and hypoxia. Its expression is inversely correlated with serum ferritin and induced by iron loading and inflammation. Hepcidin dysregulation is the underlying cause of several iron disorders. Erythropoietic activity is the main regulator of hepcidin transcription by stimulating erythropoiesis and increasing iron absorption via hepcidin downregulation. Chromatin immunoprecipitation analysis showed that the binding of CCAT enhancer binding protein (C/EBPa) to the hepcidin promoter was reduced after EPO supplementation. This indicates C/EBPa effects on hepcidin transcription in response to erythropoiesis stimulation ^[23]. Apart from that, erythropoietin levels increased under hypoxic conditions, involving hypoxia-inducible factor (HIF) in hepcidin regulation ^[14]^[19]. Furthermore, higher erythropoiesis activity and GDF15 are responsible for low hepcidin levels instead of high EPO levels ^[24].

GDF15, TWSG1, and ERFE have been reported as suppressors of hepcidin in β-thalassemia and other iron-containing anemia ^[14]. GDF15 was initially thought to be a macrophage inhibitory cytokine but it was later proven that its increase indirectly contributes to iron overload in cancer patients and those with sideropenic anemia by downregulating hepcidin expression and increasing iron absorption ^[25]^[26]. The tumor suppressor p53 drives GDF15, and its expression in the human body increases under stressful conditions, such as hypoxia, cancer, and tissue damage ^[27]^[28]. In addition, pregnancy is associated with low serum hepcidin levels in animal models and humans ^[29], which positively correlates with GDF15. In contrast, hepcidin is negatively correlated with EPO and hemojuvelin (HJV) during pregnancy ^[30]. Mutant TFR2 and HJV were associated with hepcidin suppression after hemorrhage and high levels of ERFE mRNA in the th3/+ β-thalassemia mouse model. The significance of ERFE needs to be further evaluated in different conditions of IE and iron loading anemia ^[31]^[32].

TWSG1 is higher in immature red cell precursors and mice with β-thalassemia. This erythrokine inhibits hepcidin transcription by inhibiting the BMP 2/4 pathway of SMAD (structurally similar to the small mothers against decapentaplegic in Drosophila) 1/5/8 phosphorylation ^[19]. Atonal basic helix–loop–helix (bHLH) transcription factor 8 (ATOH8) has been identified as a candidate for activation of liver hepcidin transcription ^[33]. Hypoxia, hemolysis, hypotransferrinemia, and erythropoietin treatment enhanced erythropoiesis activity and decreased ATOH8 levels in mice. However, erythropoiesis inhibitors increased ATOH8 levels, suggesting the interference between erythropoiesis and hepcidin regulation ^[33].

Inflammatory cytokines mainly induce hepcidin transcription by activating the STAT3 signaling pathway ^[34]. The BMP–SMAD signaling pathway also plays an essential role in regulating hepcidin transcription. Binding of BMPs (BMP2,4,5,6) to type I or type II serine or threonine kinase receptors leads to intracellular R-SMADS (SMAD1, 5 and 8) phosphorylation, which, in turn, binds to SMAD4 (Co-SMAD) to promote its nucleus translocation, thus activating the hepcidin transcription. Furthermore, iron management in the body activates BMP/SMAD and hepcidin signaling ^[35]. Andriopoulos et al. reported that BMP6 physically interacts with HJV and induces hepcidin to lower serum iron in mice ^[36]. HFE is also involved in hepcidin pathway regulation ^[37]^[38]. Mutations in HFE genes involved in the regulation of iron homeostasis cause type I hereditary hemochromatosis (HH) ^[39]. Additionally, an HFE-deficient mouse develops an iron overload phenotype similar to type I HH in humans ^[38]. These findings suggest that HFE positively modulates hepcidin expression ^[40]. Besides, HFE interacts with transferrin receptor 1 (TfR1) and contends with the receptor’s transferrin (Tf) binding site ^[41], resulting in the activation of downstream signaling pathways, such as the mitogen-activated protein kinase (MAPK) pathway ^[35]. Moreover, the crosstalk between the activated MAPK pathway and the BMP/SMAD pathway enhances hepcidin expression ^[42].

2.3. Hepcidin Therapeutics in β-Thalassemia

The current treatment of iron overload in β-thalassemia patients includes the administration of iron chelators, such as deferiprone, deferasirox, and desferrioxamine ^[43]^[44]. Chelation therapy is recommended in patients with serum ferritin greater than 1000 ng/mL ^[45]. The direct scavenging of LPI and NTBI by chelators helps prevent adverse sequelae of iron overload ^[46]. On the other hand, splenectomy has been recommended when the transfusion requirement increases and worsens anemia ^[47]. Besides, the allogenic hematopoietic stem cell transplantation can also be a therapeutic option for hereditary β-thalassemia, but 60% of patients lack suitable donors, thus increasing the risk of developing transplant-related complications ^[48].

The correlation between iron overload and hepcidin has led to new approaches that target the disease pathophysiology, aiming to reduce iron overload and IE ^[49]. A previous study on β-thalassemia mice indicated that a rise in hepcidin level lowers iron bioavailable to erythroblasts, resulting in decreased heme synthesis and improved erythroid precursor and reticulocyte survival ^[50]. Furthermore, decreasing hepcidin levels in thalassemia leads to iron overload and restores hepcidin to normal and, hence, is a novel therapeutic approach for thalassemia patients ^[13]. The ligand of the BMP6 receptor is involved in hepcidin regulation and transcription ^[51]. Meanwhile, transferrin is a limiting factor and restricts iron availability for erythropoiesis ^[52]. TMPRSS6 is a negative regulator of hepcidin, and its depletion using small interfering ribonucleic acid siRNA increased hepcidin mRNA and improved erythropoiesis in a β-thalassemia mouse model ^[53]. Furthermore, the SiRNA therapy decreases TMPRSS6 expression, thus increasing hepcidin expression and improving the incidence of disease-related thalassemia ^[54]. Moreover, it is reported that the combined administration of iron chelator deferiprone for RNAi targeting TMPRSS6 can significantly reduce iron content in the liver and increase the efficiency of erythropoiesis in β-thalassemia mice ^[46]^[55].

3. TGF-β/SMAD Signaling

SMADs are proteins that are activated by the transforming growth factor β (TGF-β), BMP signaling, to mediate cell proliferation and differentiation ^[56]^[57]. Endosome-associated Fab1 (yeast orthologue of PIKfyve, YOTB, vesicle transport protein (Vac1), and EEA1 (FYVE zinc finger domain)-domain protein (endofin)) influences hepcidin expression by regulating SMAD1/5/8 phosphorylation ^[58]. STAT and SMAD signaling regulate hepcidin expression ^[59]. Ablation of SMAD4, specifically in the liver, triggers an iron overload in multiple organs due to decreased levels of liver hepcidin ^[60]. However, SMAD7 acts as an effective inhibitor of hepcidin mRNA expression through a negative regulation effect on TGF-β and BMP/SMAD signaling ^[61]^[62]. TGF-β is the prototypical ligand of the TGF-β superfamily, which signals during activation of serine/threonine receptor kinases. This superfamily is subdivided into the TGFβ/activin branch and BMP/growth and differentiation factor (GDF) branch.

TGF-β is expressed in most cell types and translated into a proprotein that is proteolytically cleaved into a noncovalently linked mature TGF-β and latency-associated protein (LAP) ^[63]^[64]. The active TGF-β ligand is a 25 kDa dimer, covalently linked by bisulfide bonds between cysteine residues of each monomeric peptide ^[63]^[64].

Various mechanisms are used to regulate the bioavailability of TGF-β in vivo. Once the bioavailable TGF-β reaches the target cell’s surface, it bonds with the homodimer of TGF-β type II receptor (TβRII) ^[65]. The TGF-β–TβRII complex provides a structural interface that forms a stable complex with the homodimer of the TGF-β type I receptor (TβRI) ^[56]. Subsequently, the active receptor–ligand complex is a heterotetrametric complex composed of TGFβ dimer and homodimer of TβRII and TβRI. In the active receptor complex, TβRII is constitutively activated and stimulates the transphosphorylation of TβRI ^[56]^[66]. In the TGF-β pathway, SMAD2 and SMAD3 are receptor-regulated effector proteins (R-SMADs) phosphorylated by activated TβRI on the C-terminal SSXS motif, leading to the nuclear accumulation of R-SMAD ^[56].

The activated receptor complex bound to the ligand is internalized by endocytosis ^[67]. Internalization of cell surface receptors can occur through clathrin-mediated or caveolae-mediated endocytosis ^[68].

Upon ligand stimulation, the SMADs accumulate in the nucleus as R-SMAD/CO-SMAD complex, leading to a decrease in their nuclear export rate ^[69]^[70]. The SMAD complex binds to DNA with other transcription factors and interacts with the general transcription machinery to regulate the expression of target genes (Figure 1) ^[71].

Figure 1. Signal transduction of TGF-β and BMP. The binding of TGF-β to the TβRII dimer allows the ligand to bind to the TβRI dimer and stimulate TβRI kinase activity. In SMAD-mediated TGF-β signal transduction, TβRI phosphorylates cytoplasmic SMAD2 and SMAD3, which interact with SMAD4 after dissociating from TβRI. The two receptors activate the trimeric complex of SMAD2 and SMAD3, and a SMAD4 then enters the nucleus, where it interacts with the DNA-binding transcription factor (TF) and coregulators of the target gene. Similarly, the BMP signals run parallel to the TGF-β signals. In response to the binding of the BMP ligand to the BMPRII heteromeric receptor complex and BMPRI transmembrane kinase, receptor-activated SMAD1 and SMAD5 bind to SMAD4 and are transported to the nucleus to activate or inhibit transcription of hepcidin. ➔: Activation and ⊥: Inhibit.

Signaling pathways such as signal transducers and activators of transcription (STAT) and SMAD regulate the expression of hepcidin. Therefore, it is hypothesized that STAT and SMAD could be dephosphorylated in thalassemia cases, including HbE/β-thalassemia patients, resulting in hepcidin downregulation with the presence of iron accumulation.

4. Conclusions

In summary, iron homeostasis dysregulation has a dominant physiological effect on transfusion-dependent and transfusion-independent β-thalassemia patients. Thus, understanding the expression of hepcidin and its regulation in β-thalassemia patients is vital in developing rational therapeutic interventions to provide safe, effective, and lifelong treatment options for their management. Therefore, recovery of hepcidin in β-thalassemia patients through the activation of STAT 3, STAT 5, SMAD 1/5/8, and SMAD 4 signaling could be a potential therapeutic target for managing iron overload (Figure 2). Therefore, it is highly recommended for future preclinical and clinical studies to evaluate the related risks and benefits of hepcidin-targeted treatment approaches.

Figure 2. Regulation of STAT and SMAD signaling pathway on hepcidin expression.

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Hamid Al-Jamal

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