Iron overload inhibits osteogenic commitment and differentiation of mesenchymal stem cells via the induction of ferritin.
Osteogenic differentiation of multipotent mesenchymal stem cells (MSCs) plays a crucial role in bone remodeling. Numerous studies have described the deleterious effect of iron overload on bone density and microarchitecture. Excess iron decreases osteoblast activity, leading to impaired extracellular matrix (ECM) mineralization. Additionally, iron overload facilitates osteoclast differentiation and bone resorption. These processes contribute to iron overload-associated bone loss. In this study we investigated the effect of iron on osteogenic differentiation of human bone marrow MSCs (BMSCs), the third player in bone remodeling. We induced osteogenic differentiation of BMSCs in the presence or absence of iron (0-50μmol/L) and examined ECM mineralization, Ca content of the ECM, mRNA and protein expressions of the osteogenic transcription factor runt-related transcription factor 2 (Runx2), and its targets osteocalcin (OCN) and alkaline phosphatase (ALP). Iron dose-dependently attenuated ECM mineralization and decreased the expressions of Runx2 and OCN. Iron accomplished complete inhibition of osteogenic differentiation of BMSCs at 50μmol/L concentration. We demonstrated that in response to iron BMSCs upregulated the expression of ferritin. Administration of exogenous ferritin mimicked the anti-osteogenic effect of iron, and blocked the upregulation of Runx2, OCN and ALP. Iron overload in mice was associated with elevated ferritin and decreased Runx2 mRNA levels in compact bone osteoprogenitor cells. The inhibitory effect of iron is specific toward osteogenic differentiation of MSCs as neither chondrogenesis nor adipogenesis were influenced by excess iron. We concluded that iron and ferritin specifically inhibit osteogenic commitment and differentiation of BMSCs both in vitro and in vivo.
Department of Internal Medicine, Faculty of Medicine, University of Debrecen, 98. Nagyerdei Krt., 4012 Debrecen, Hungary.
Enikő
E
Balogh
Department of Internal Medicine, Faculty of Medicine, University of Debrecen, 98. Nagyerdei Krt., 4012 Debrecen, Hungary.
Emese
E
Tolnai
Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 98. Nagyerdei Krt., 4012 Debrecen, Hungary.
Béla
B
Nagy
Department of Pediatrics, Faculty of Medicine, University of Debrecen, 98. Nagyerdei Krt., 4012 Debrecen, Hungary.
Béla
B
Nagy
Department of Pediatrics, Faculty of Medicine, University of Debrecen, 98. Nagyerdei Krt., 4012 Debrecen, Hungary.
György
G
Balla
Department of Internal Medicine, Faculty of Medicine, University of Debrecen, 98. Nagyerdei Krt., 4012 Debrecen, Hungary.
József
J
Balla
Department of Internal Medicine, Faculty of Medicine, University of Debrecen, 98. Nagyerdei Krt., 4012 Debrecen, Hungary. Electronic address: jeneyv@belklinika.com.
Viktória
V
Jeney
D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002113:Calcification, Physiologic / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005293:Ferritins / Q000096:biosynthesis* / Q000494:pharmacology; D006801:Humans; D007501:Iron / Q000008:administration & dosage; D019190:Iron Overload / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D010710:Phosphates / Q000378:metabolism / Q000494:pharmacology
D050659:Core Binding Factor Alpha 1 Subunit; D010710:Phosphates; D015675:Osteocalcin; D005293:Ferritins; D007501:Iron; D000469:Alkaline Phosphatase; D002118:Calcium
Ferritin; Human mesenchymal stem cell; Iron; Osteogenic differentiation; Runx2