The role of iron in heterotopic ossification

Introduction: Heterotopic ossification (HO) is bone formation at abnormal anatomical sites, developing in three main stages: inflammation, chondrogenesis and osteogenesis. Bone morphogenetic protein (BMP) signaling plays an important role in the pathogenesis of HO. As the BMP pathway has also emerged as an important regulator of iron homeostasis, we aimed to investigate the impact of iron levels on HO development.

Methods: For this purpose, wild type mice were fed with either low (<10 ppm Fe), normal (200 ppm Fe) or high (25,000 ppm Fe) iron diet for 8 weeks starting from weaning on. HO was then induced by injection of recombinant BMP-2 into the M. tibialis anterior. Bone formation in the muscle was assessed after 14 days by µCT analysis. Iron measurements of the inner organs and the muscle were performed at day 0 and 14 after HO induction. Additionally, a proteome cytokine profiler was performed at day 3.

Results: High iron diet in WT mice led to a 2.6-fold increase in HO 14 days after BMP-2 injection (p<0.05), while low iron diet led to a 65 %-decrease of bone formation (p<0.05) compared to normal iron diet. In mice fed with high iron diet, iron accumulated in the inner organs such as liver (2001.61 vs 280.66 µg Fe/g dry tissue, p<0.001) and spleen (3680.68 vs 1427.70 µg Fe/g dry tissue, p<0.01) as well as in the muscle (0.14 vs 0.69 µg Fe/ mg protein, p<0.001). Analyzing the proteome in the inflammatory phase of HO mice fed with a high iron diet, we found several pro-inflammatory cytokines increased, e.g. IL-33 (1.67-fold change, p<0.01), IFNγ (2-fold increase, p<0.05), IL-6 (1.75-fold increase, p<0.05) and Osteoprotegerin (2.26-fold change, p<0.05).

Discussion: Iron levels especially, high iron levels affect the development of HO, most likely already in the early inflammatory stage of HO by increasing pro-inflammatory cytokines.

Keywords: heterotopic bone formation, iron levels, BMP signaling

Korrespondenzadresse: Sven Spangenberg, Department of Medicine III & Center for Healthy Aging, Medical Faculty and University Hospital Carl Gustav Carus, Fetscherstraße 74, 01307 Dresden, Germany, E-Mail: [e-mail]

Publication History

Article published online:
13 March 2024