RGM-C: A Key Regulatory Protein in the Iron Metabolism Pathway

Hepcidin is the core regulatory hormone for systemic iron balance, primarily secreted by hepatocytes. Under normal physiological conditions, elevated circulating iron levels significantly induce the liver to upregulate hepcidin expression. High levels of hepcidin can reduce intestinal iron absorption and inhibit the release of iron from tissue stores into the blood, avoiding iron overload and abnormal distribution. Conversely, when circulating iron is insufficient, hepcidin synthesis is downregulated, promoting the release of usable iron from duodenal epithelial cells and tissue iron stores. Dysregulation of hepcidin expression can induce various diseases; hepcidin deficiency leads to iron-loading anemias such as Juvenile Hemochromatosis (JH) and thalassemia, whereas excess hepcidin induces Anemia of Inflammation (AI) and Iron Refractory Iron Deficiency Anemia (IRIDA). Studies have shown that hemojuvelin (also known as RGM-C/HJV) can positively regulate hepcidin expression, making it a key target for the development of drugs for diseases associated with abnormal iron metabolism^[1][2].

Structure and Function of RGM-C/HJV

RGM-A, RGM-B, and RGM-C all belong to the repulsive guidance molecule (RGM) family. Among them, RGM-A and RGM-C contain an RGD motif, and all RGM members contain a vWF type D domain (featuring a highly conserved self-cleavage site, FGDPH) and a C-terminal glycosylphosphatidylinositol (GPI) anchor sequence. RGM-A and RGM-C can undergo autocatalytic hydrolysis at the FGDPH site, forming two fragments connected by a disulfide bond. Research indicates that RGM-A primarily exists as a two-chain form, while RGM-B is a single-chain form. Unlike the other two, RGM-C contains a furin-like proprotein convertase (PPC) recognition and cleavage sequence at its C-terminus. This allows it to undergo a series of complex biosynthetic and processing steps to ultimately form four different protein isoforms: two membrane-bound forms (one is a disulfide-linked two-chain form, and the other is a single-chain form) and two soluble single-chain forms (where the low-molecular-weight soluble RGM-C is generated by PPC hydrolytic cleavage of the high-molecular-weight form, both originating from the membrane-bound single-chain RGM-C)^[3][4].  

Schematic Diagram of RGM Family Members' Structures^[3] (Green represents the RGD motif, yellow represents the vWF D domain, purple represents the PPC recognition and cleavage site, and solid arrows represent the protein self-cleavage sites)

As co-receptors for bone morphogenetic proteins (BMP), RGM family members can selectively bind to BMP ligands; notably, RGM-C has the highest affinity for BMP6, and the BMP6-RGM-C-SMAD signaling pathway it mediates is the core signaling axis regulating hepcidin expression. When the body's iron is sufficient, circulating BMP6 binds with BMP type I receptors (BMPRI), BMP type II receptors (BMPRII), and RGM-C on the surface of hepatocytes to form a complex, activating the SMAD signaling cascade. Intracellularly activated SMAD1/5/8 forms a complex with the common mediator SMAD4 and enters the nucleus, binding to the BMP response element (BMPRE) in the hepcidin promoter region to induce hepcidin expression. Furthermore, under inflammatory conditions, pro-inflammatory cytokines like IL-6 bind to their receptors and initiate signal transduction via activated JAK1/2 proteins, leading to the phosphorylation and activation of the transcription factor STAT3. Activated STAT3 can bind to the STAT3 response element (STAT3RE) on the proximal promoter of hepcidin. The synergistic regulation by BMPRE and STAT3RE jointly mediates the inflammation-induced high expression of hepcidin. As a negative regulator of iron metabolism, hepcidin, upon secretion into the blood, inhibits the iron export function of ferroportin (FPN), ultimately causing iron retention in reticuloendothelial macrophages and decreased iron absorption in the duodenum.  

Regulatory Roles of the BMP6-RGM-C-SMAD and IL-6-STAT3 Signaling Pathways on Hepcidin^[2]

Targeted Drug Development for RGM-C/HJV

As a co-receptor for BMP ligands, RGM-C mediates the BMP/SMAD signaling pathway and positively regulates hepcidin expression. Targeted inhibition of RGM-C can effectively downregulate hepcidin expression and elevate serum iron, providing a new strategy for treating diseases characterized by reduced circulating iron, such as anemia of inflammation. Currently, the representative drug for RGM-C is DISC0974, a monoclonal antibody drug targeting RGM-C. It was originally developed by AbbVie and later acquired for global development rights by Disc Medicine in 2019. This drug reduces the body's production of hepcidin by inhibiting RGM-C and is intended for the treatment of myelofibrosis (MF) anemia, non-dialysis-dependent chronic kidney disease anemia, and other inflammatory anemias.

DISC0974 Mechanism Diagram^[5]

A Phase 1b multicenter, double-blind, placebo-controlled, dose-escalation trial conducted in patients with non-dialysis-dependent chronic kidney disease complicated by anemia showed that DISC0974 possessed acceptable safety and tolerability across all evaluated doses. Compared with the placebo, it significantly reduced hepcidin levels and increased serum transferrin saturation (TSAT); furthermore, it increased the mean reticulocyte hemoglobin content and overall hemoglobin levels^[5].

Partial RGM-C Targeted Drugs

KACTUS Supplies High-Quality RGM-C Proteins

As a key BMP co-receptor regulating hepcidin and iron homeostasis, RGM-C is an extremely valuable and important target in the field of iron metabolism diseases. KACTUS supplies high-quality RGM-C proteins, covering different species and tags, which have undergone strict quality control. They are suitable for various application scenarios such as immunization and screening, fully accelerating the drug development of RGM-C.

Product data

Immobilized Human RGM-C, His Tag at 1μg/ml (100μl/well) on the plate. Dose response curve for Anti-RGM-C Antibody, hFc Tag with the EC50 of 3.8ng/ml determined by ELISA. (QC Test)
Immobilized Cynomolgus RGM-C, His Tag at 1μg/ml (100μl/well) on the plate. Dose response curve for Anti-RGM-C Antibody, hFc Tag with the EC50 of 1.7ng/ml determined by ELISA.

Product List

References

[1] Core AB, Canali S and Babitt JL (2014) Hemojuvelin and bone morphogenetic protein (BMP) signaling in iron homeostasis. Front. Pharmacol. 5:104. doi: 10.3389/fphar.2014.00104.
[2] Sun CC, Vaja V, Babitt JL, Lin HY. Targeting the hepcidin-ferroportin axis to develop new treatment strategies for anemia of chronic disease and anemia of inflammation. Am J Hematol. 2012 Apr;87(4):392-400. doi: 10.1002/ajh.23110. Epub 2012 Jan 31. PMID: 22290531; PMCID: PMC3653431.
[3] Severyn CJ, Shinde U, Rotwein P. Molecular biology, genetics and biochemistry of the repulsive guidance molecule family. Biochem J. 2009 Aug 27;422(3):393-403. doi: 10.1042/BJ20090978. PMID: 19698085; PMCID: PMC4242795.
[4] Tian C, Liu J. Repulsive guidance molecules (RGMs) and neogenin in bone morphogenetic protein (BMP) signaling. Mol Reprod Dev. 2013 Sep;80(9):700-17. doi: 10.1002/mrd.22199. Epub 2013 Jul 19. PMID: 23740870; PMCID: PMC4440832.
[5] Samir Arora, Jorge Monroy, Pablo Pergola, Arnold Silva, Akshay Buch, Natasha Novikov, Olivia Pelletier, William Savage; A Phase 1b Double-Blind, Placebo-Controlled Study of DISC-0974, an Anti-Hemojuvelin Antibody, in Patients with Non-Dialysis Dependent Chronic Kidney Disease and Anemia. Blood 2023; 142 (Supplement 1): 5236.