VIT-2763, a ferroportin-1 inhibitor, modulates osteoblast and osteoclast functions in hemizygous βIVSII-654 knock-in thalassemic mice with osteopenia
7 affiliations
- 1Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand
- 2Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand
- 3Physiology Division, Preclinical Science, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand
- 4Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand
- 5Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand
- 6Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand
- 7The Academy of Science, The Royal Society of Thailand, Bangkok, Thailand
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 βIVSII-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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BibTeX
@article{aeimlapa2026vit2763,
title = {{VIT-2763, a ferroportin-1 inhibitor, modulates osteoblast and osteoclast functions in hemizygous βIVSII-654 knock-in thalassemic mice with osteopenia}},
author = {Ratchaneevan Aeimlapa and Jarinthorn Teerapornpuntakit and Jirawan Thongbunchoo and Pathnaree Wattano and Jiraporn Panmanee and Saovaros Svasti and Narattaphol Charoenphandhu},
journal = {Cell Death Discovery},
year = {2026},
month = jul,
doi = {10.1038/s41420-026-03273-x},
url = {https://doi.org/10.1038/s41420-026-03273-x},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - VIT-2763, a ferroportin-1 inhibitor, modulates osteoblast and osteoclast functions in hemizygous βIVSII-654 knock-in thalassemic mice with osteopenia
AU - Ratchaneevan Aeimlapa
AU - Jarinthorn Teerapornpuntakit
AU - Jirawan Thongbunchoo
AU - Pathnaree Wattano
AU - Jiraporn Panmanee
AU - Saovaros Svasti
AU - Narattaphol Charoenphandhu
PY - 2026
DA - 2026/07/31
JO - Cell Death Discovery
DO - 10.1038/s41420-026-03273-x
UR - https://doi.org/10.1038/s41420-026-03273-x
AB - 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 βIVSII-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.
SN - 2058-7716
ER -