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By Alexander Glaros, MD, and Ahmar U. Zaidi, MD

If the results of the past five years are any indication, the era of gene therapy is truly at hand, and nearly 100 years after Thomas Cooley first described the skeletal and morphological changes of the disease in a pair of Detroit children, so, too, is a cure for thalassemia. Yet, in a century of exponentially accelerating technological advances and expanded understanding of the pathophysiology underlying the disease’s sequelae, we still do not have a complete understanding of the mechanisms behind the bony changes Cooley identified.

While it is known that the bone marrow space is expanded as enhanced intra- and extra-medullary hematopoiesis compensates for chronic hemolytic anemia, this has never fully explained all of the skeletal abnormalities. As we await the proven efficacy, safety, and widespread availability of the gene therapies we’ve heard so much about, it is our duty to continue exploring the intricacies of thalassemia for those who continue to be affected around the world, and for those who may have to wait decades to easily access a cure. One such dedicated investigator who has uncovered one of thalassemia’s long-hidden secrets, Melanie Castro-Mollo, MS, of Icahn School of Medicine at Mount Sinai, revealed her preliminary data on Sunday afternoon (Plenary abstract #2). In the abstract titled, Erythroferrone Regulates Bone Remodeling in β-Thalassemia, Dr. Castro-Mollo presented her team’s research into a molecular explanation for the skeletal changes of thalassemia, including some new and exciting insights into the hormone’s role beyond its known involvement in iron homeostasis. Patients with β-thalassemia are known to have low bone mass due to decreased mineral density and cortical thinning, even as the medullary cavity expands, but the role of erythroferrone (ERFE) in causing these changes was unexplored until now. The widely recognized role of the hormone in the body is the suppression of hepcidin via the sequestration of bone morphogenetic protein — a positive regulator of hepcidin via its interaction with hemojuvelin. It has long been known to be produced by erythroblasts, thereby increasing iron availability for hematopoiesis as the inhibition by hepcidin on iron absorption is removed. Dr. Castro-Mollo and colleagues made the exciting discovery that BMPs are also produced by osteoblasts to varying degrees throughout their maturation process, at even higher levels than those produced by erythroblasts. This discovery led to the hypothesis that ERFE regulates bone formation and remodeling by a mechanism yet to be fully elucidated. To explore their hypothesis, ERFE knockout mice, both with and without thalassemia, were studied. Surprisingly these mice were found to have low bone mass. This result was unexpected, as the thought was that by losing ERFE there would be no sequestration of BMPs, and as a result, higher bone mass, thus directly implicating ERFE as a culprit in the low bone mass of thalassemia. It was confirmed that ERFE loss did result in decreased BMP, but its loss in osteoblasts also resulted in increased production of sclerostin, which has a role in increasing osteoclastogenesis via RANKL upregulation. The increased density of osteoclasts appeared to be the explanation for the decreased bone mineral density, as cortical sampling from ERFE–/– mice did reveal an increased density of osteoclasts. The exact mecha- nism behind this process is still under investigation, but Dr. Castro-Mollo suspects it could be that only certain types of BMPs are directly affected by changes in ERFE, altering the overall BMP signaling environment and thus the activity of osteoblasts and osteoclasts. ERFE, as it turns out, is not the culprit when it comes to low bone density in thalassemia, but it is in fact protective against even worse damage. This seminal work is an important clue to the mechanisms of bone remodeling in thalassemia, with more clarity hopefully to come. Dr. Castro-Mollo would like to take this research in several directions in the future, including the investigation of other hematologic diseases with bone remodeling as a recognized sequela (e.g., multiple myeloma, myelofibrosis), as well as the exploration of the wnt pathway as it relates to bone remodeling.                                                              

Dr. Glaros and Dr. Zaidi indicated no relevant conflicts of interest.

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