Iron overload inhibits osteogenic commitment and differentiation of mesenchymal stem cells via the induction of ferritin

Eniko Balogh, Emese Tolnai, Béla Nagy, B. Nagy, G. Balla, J. Balla, V. Jeney

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

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 (0-50 μmol/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 50 μmol/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.

Original languageEnglish
Pages (from-to)1640-1649
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1862
Issue number9
DOIs
Publication statusPublished - Sep 1 2016

Keywords

  • Ferritin
  • Human mesenchymal stem cell
  • Iron
  • Osteogenic differentiation
  • Runx2

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine

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