Erythroferrone may function as negative regulator of bone remodeling in beta-thalassemia
ORLANDO — Erythroferrone appeared to function as a negative regulator of osteoblast and osteoclast activity, and its loss can result in decreased bone mineral density in beta-thalassemia, according to results of a study presented during the plenary session of ASH Annual Meeting and Exposition.
The findings may provide new insights into the interaction between regulation of iron metabolism and bone homeostasis in diseases of dysregulated erythropoiesis, researchers wrote.
Erythropoiesis usually occurs in bone marrow within the femur and pelvis, and erythropoiesis and bone metabolism are vulnerable to changes in iron homeostasis. Because of this, hematopoietic and osteoid systems rely upon iron metabolism coordination during stress or ineffective erythropoiesis.
Studies looking at the communication between iron metabolism and erythropoiesis showed that erythroferrone (ERFE), a bone marrow-secreted protein, is a negative regulator of hepcidin. Hepcidin is the central negative regulator of iron absorption and recycling. Suppressing it allows for more iron availability during stress erythropoiesis.
Diseases that cause ineffective erythropoiesis, such as beta-thalassemia, with chronic erythroid expansion, are associated with decreased bone mineral density. Patients and mouse models present increased levels of ERFE, which functions by sequestering bone morphogenic protein (BMP), specifically BMPs 2/5/6 and 7. Also, BMPs have a crucial role in bone formation and osteoblast differentiation.
“The mechanism of activation of ERFE, BMP sequestration, occurs in the bone remodeling process. So, basically, that is how we started this project,” Melanie Castro-Mollo, MD, graduate student at Icahn School of Medicine at Mount Sinai, told Healio. “We wanted to test the mechanism of ERFE related to bone metabolism.”
Results showed that among thalassemic mice, those with ERFE loss had decreased bone mineral density (P < .05), as well as a decreased ratio of bone volume to total volume.
Osteoclast activity also was increased in mice with ERFE loss and thalassemic mice with ERFE loss compared with wild-type and thalassemic mice.
Additionally, researchers observed that ERFE is secreted by osteoblasts and osteoclasts and the secreted ERFE was functional, leading to suppression of hepcidin tested in hepatocytes.
ERFE loss in osteoblast led to an upregulation of sclerostin, which is a Wnt inhibitor resulting in decreased bone formation, Castro-Mollo said.
“We were surprised at these results. We thought for sure there was something else going on to get these results,” Castro-Mollo told Healio. “We are still going to be working with mice for some time because we still need to answer many questions, including the relationship with TfR2, the effect of ERFE in osteoclasts, and the effect of whether iron in bone marrow changes with ERFE. There are many diseases that involve bone changes, including myelodysplastic syndrome, so we should get the whole idea behind what’s going on.” – by John DeRosier
Castro-Mollo M, et al. Abstract 2. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosures: Castro-Mollo reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.