Iron Overload Induces Oxidative Stress, Cell Cycle Arrest and Apoptosis in Chondrocytes.

Asima Karim,Mawieh Hamad,Khuloud Bajbouj,Rizwan Qaisar,Jasmin Shafarin,Andrew C Hall

doi:10.3389/fcell.2022.821014

Abstract

Clinical and experimental evidence point to the presence of considerable links between arthropathy, osteoarthritis (OA) in particular, and iron overload possibly due to oxidative stress and tissue damage. However, the specific cellular targets of iron overload-related oxidative stress in OA remain ambiguous. We examined the effects of iron overload on chondrocyte health using the C-20/A4 chondrocyte cell line. Cells were treated with increasing concentrations of ferric ammonium citrate (FAC) to mimic iron overload in vitro. Treated cells were assessed for cell viability, cycling, apoptosis, collagen II synthesis, and oxidative stress along with cellular iron content and the expression of key iron regulatory genes. FAC treatment resulted in an increase in ferritin expression and a significant decrease in the expression of hepcidin, ferroportin, transferrin receptors 1 (TfR1) and TfR2. Increased labile iron content was also evident, especially in cells treated with high FAC at 24 h. High doses of FAC treatment also induced higher levels of reactive oxygen species, reduced collagen II production, disrupted cell cycle and higher cell death as compared with untreated controls. In conclusion, findings presented here demonstrate that iron overload disrupts cellular iron homeostasis, which compromises the functional integrity of chondrocytes and leads to oxidative stress and apoptosis.

Highlights

Osteoarthritis (OA) is a common joint disease which typically causes severe pain and disability (Vina and Kwoh, 2018)
In this preliminary set of experiments, we evaluated the impact of iron overload on chondrocyte viability in vitro using the ferric ammonium citrate (FAC)-treated human chondrocyte cell line C-20/A4
We found that chondrocytes with iron overload demonstrated increased cell death, a hallmark of OA pathogenesis

Summary

Introduction

Osteoarthritis (OA) is a common joint disease which typically causes severe pain and disability (Vina and Kwoh, 2018). Old age (Li et al, 2013; Loeser, 2017) and disrupted iron homeostasis (Burton et al, 2020) are believed to be significant contributing factors in the initiation and/or exacerbation of OA (Nugzar et al, 2018). Hereditary hemochromatosis (HH), which associates with excessive iron accumulation in body tissues and organs due to the inheritance of one or more mutations in the Human homeostatic iron regulator (HFE) gene, has been shown to lead to OA-like arthropathy (Carroll et al, 2011). The presence of high ferritin levels and excessive iron accumulation has been documented in the synovial fluid and articular cartilage/synovial membranes of HH patients showing signs of OA (Dejaco et al, 2017; Simão et al, 2019).

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Conclusion