VIT-2763, a ferroportin-1 inhibitor, modulates osteoblast and osteoclast functions in hemizygous βIVSII-654 knock-in thalassemic mice with osteopenia

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Abstract Iron overload is a serious complication of thalassemia that affects various organ functions. Although iron chelators effectively alleviate iron overload, they have some adverse effects on bone structure. VIT-2763, an oral ferroportin-1 inhibitor, has been recently reported to reduce iron overload and improve ineffective erythropoiesis in β-thalassemia. Since iron is required for osteoblast and osteoclast functions, VIT-2763 was hypothesized to modulate bone metabolism. Herein, we used hemizygous β IVSII-654 knock-in thalassemic (B654) mice as a model of β-thalassemia with skeletal defects including trabecular bone loss and cortical thinning. At the cellular level, mRNA expression of bone formation-related genes (e.g., Runx2, ALP, osteocalcin) was upregulated in B654-derived primary osteoblasts. The mRNA expression of those bone formation-related genes was negatively correlated with ferroportin-1 expression in primary osteoblasts. In primary osteoclasts, the mRNA expression of mature osteoclast-specific genes was positively correlated with ferroportin-1 expression, suggesting an involvement of ferroportin-1 in regulating bone formation and resorption. We further showed that VIT-2763 effectively suppressed ferroportin-1 protein expression in both primary osteoblasts and osteoclasts. VIT-2763 decreased viability of primary osteoblasts without affecting osteoblast-specific gene expression and bone mineralization. Interestingly, VIT-2763 biphasically regulated osteoclastogenesis, particularly in early osteoclast differentiation, and attenuated osteoclast-mediated bone resorption in vitro. Quantitative analysis of three-dimensional (3D) osteoclastic hologram images found that VIT-2763 significantly altered cellular properties (e.g., mean refractive index) of primary osteoclasts in iron-loaded conditions. In conclusion, modulation of ferroportin-1 expression and cellular functions by VIT-2763 potentially inhibited osteoclast-mediated bone resorption. It may be a novel anti-resorptive agent for treating iron-induced osteopathy in β-thalassemia.

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Related topics: Hemoglobinopathies and Related Disorders · Iron Metabolism and Disorders · Bone Metabolism and Diseases