Hepcidin in iron metabolism: at San Raffaele discovered a new mechanism of regulation

Despite presenting different clinical manifestations, fibrodysplasia ossificans progressiva (FOP) and pulmonary arterial hypertension (PAH) share some common aspects, whose study might help the developing of new therapies for other diseases, as iron overload pathologies.

The research, published in “Blood and funded by Telethon, is explained by Dr. Silvia Colucci, first author of the article. Silvia is a former student of Biotechnology at our University and currently a PhD student in Heidelberg, Germany, in the Iron Homeostasis group, part of the Molecular Medicine Partnership Unit (MMPU).

HOW THE IDEA OF THIS RESEARCH IS BORN

This research” says Dr. Colucci “was born from an idea of Dr. Laura Silvestri, Project leader at the  “Regulation of Iron Metabolism” Unit (coordinated by Prof. Clara Camaschella, Division of Genetics and Cell Biology), and supervisor of the Master thesis during my internship. Following an excellent intuition, she managed to put together pieces of a puzzle that at first seemed absolutely unrelated”.

FOP and PAH have a common aspect: the alteration of the BMP-SMAD signaling pathway.

pathway_eng

What is it about?

BMP” (which stands for “bone morphogenetic proteins”) is the name of a group of molecules with different functions. When BMPs interact with ALK2, a plasma membrane receptor expressed in some cells, they activate a signaling cascade (that involves a class of proteins named SMAD) thus regulating the expression of BMP-SMAD target genes.

The BMP-SMAD signaling is extremely important in iron metabolism. It regulates the expression of hepcidin, a hormone produced by the liver that modulates the absorption and redistribution of iron to the whole body. The inappropriate regulation of hepcidin causes iron deficiency, and therefore anemia, or iron overload, extremely toxic for all the organs of our body. The identification of mechanisms able to modulate hepcidin is particularly important to ameliorate the phenotype of diseases characterized by a dysregulation of this hormone”.

WHAT IS THE MAIN TOPIC OF THIS STUDY?

The authors identified a novel fundamental player in the regulation of iron metabolism: “FKBP12 is a protein able to bind and inhibit receptors of the BMP-SMAD pathway, in particular ALK2: in this research we investigated whether FKBP12 is involved in the modulation of the liver BMP-signaling pathway and therefore in the regulation of hepcidin”.

The authors adopted two complementary experimental approaches: “We have generated mutated forms of ALK2 unable to interact with FKBP12, and used different drugs (tacrolimus, rapamycin and GPI-1046) able to bind FKBP12 and to prevent its interaction with ALK2”.

fkbp12_eng

“By using these approaches, we were able to increase hepcidin expression through BMP-SMAD pathway activationsays Colucci, “both in human hepatoma [liver tumor, Editor’s note] and primary murine hepatocytes [liver cells, Editor’s note]”. The work thus demonstrated that FKBP12, by interacting with ALK2, modulates the activity of the BMP-SMAD pathway and therefore the expression of hepcidin in hepatocytes.

POTENTIAL CLINICAL IMPLICATIONS OF THIS STUDY

The potential clinical implications resulting from the identification of a new hepcidin regulator are extremely relevant. “Low levels of hepcidin cause iron overload and therefore functional damage to several organs such as liver, heart, pancreas. Excess iron is toxic and can cause fatal organ failure, as in Hereditary Hemochromatosis and β-thalassemia. The current therapeutic approach – aimed at reducing the total amount of iron in the body – does not correct the primary defect, i.e. the reduced hepcidin production”. Dr. Colucci highlights: “In the case of hemochromatosis, the first choice therapy is phlebotomy, i.e. the removal of a certain amount of blood (and therefore iron). In the case of β-thalassemia, where phlebotomy is not feasible because of anemia, iron chelators are administered. These therapeutic approaches, however, are not applicable to all patients because of potentially severe side effects.

The “Regulation of iron metabolism” Unit team. Dr. Silvestri is the first from left; Silvia Colucci is besides her
The “Regulation of iron metabolism” Unit team. Dr. Silvestri is the first from left; Silvia Colucci is besides her

Drugs able to interfere or reduce the interaction of FKBP12 with ALK2 would therefore increase hepcidin and might be useful for those patients that do not tolerate traditional therapies. FDA-approved drugs able to bind and sequester FKBP12 are already available, as the immunosuppressive tacrolimus and rapamycin: for these drugs, it may be possible a “drug repurposing” strategy [is the process of redeveloping a compound for use in a different disease, Editor’s note]”.

A “UNISR METHOD”-PHD

Finally, we ask Silvia how UniSR has provided the skills and tools to pursue her doctorate abroad. “During the university I have learned how to approach the scientific problems: I believe this is the most important aspect that allowed me to deal with a PhD (not necessarily abroad). In addition to the basics, the great teaching I have received was the method to be used in facing each aspect of science that interests me. Another essential element was certainly the thesis internship, which lasts a minimum of 12 months in our University: being actively involved in the daily laboratory life was of pivotal importance to me. I would like to thank Prof. Clara Camaschella, Dr. Laura Silvestri and all the colleagues of the “Regulation of Iron Metabolism” Unit for having taught me how to work and instilled in me how beautiful and exciting this job is”.

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