Iron Overload Is Associated With Accelerated Progression of Osteoarthritis: The Role of DMT1 Mediated Iron Homeostasis

Xingzhi Jing,Xingzhi Jing,Xiaoyang Liu,Xiaoyang Liu,Guodong Wang,Guodong Wang,Ting Du,Xingang Cui,Xingang Cui,Xingang Cui,Zhensong Jiang,Zhensong Jiang,Jiamin Lin,Tao Li,Tao Li,Kai Sun,Kai Sun

doi:10.3389/fcell.2020.594509

Abstract

Objective: Iron overload is common in elderly people which is associated with an increased prevalence of osteoarthritis (OA), but the exact role of iron in the development of OA has not been established. The aim of the present study is to elucidate the connection between iron overload and OA using an iron overloaded mice model, as well as to explore the role of iron homeostasis, iron transporters dependent iron influx in OA pathogenesis.Methods: The iron overloaded mice model was established and OA was surgically induced. OA progression was assessed at 8 weeks after surgery. Next, primary chondrocytes were treated with pro-inflammatory cytokines and iron regulators mediated iron homeostasis were evaluated. Involvement of iron transporters was analyzed using chondrocytes mimicking an osteoarthritis-related phenotype in vitro.Results: Iron overloaded mice exhibited greater cartilage destruction and elevated ADAMTS5 as well as MMP13 expression along with increased iron accumulation and dysregulated iron regulators. Pro-inflammatory cytokines could disturb cellular iron homeostasis via upregulating iron import proteins, TFR1 and DMT1, downregulating iron efflux protein FPN, thus result in cellular iron overload. Among iron transporters, DMT1 was found to play pivotal roles in iron overload induced OA progress. Inhibition of DMT1 suppressed IL-1β induced inflammatory response and ECM degradation via blockade of MAPK and PI3K/AKT/NF-κB pathways.Conclusions: Our results suggest that iron takes parts in the development of OA and cutting iron influx via inhibiting DMT1 activity could be an attractive new target for OA treatment.

Highlights

Osteoarthritis (OA) is a chronic degenerative joint disease which is characterized by progressive loss of joint cartilage and subchondral bone remodeling
We found that disruption of iron homeostasis took parts in the onset and progression of OA and divalent metal transporter 1 (DMT1) was found to play pivotal roles in iron overload induced OA progression
Serum and liver iron content were markedly increased in iron overloaded mice with up to 12- and 110-fold when compared to their controls (Figures 1A,B)

Summary

Introduction

Osteoarthritis (OA) is a chronic degenerative joint disease which is characterized by progressive loss of joint cartilage and subchondral bone remodeling. Hereditary hemochromatosis (HH) is caused by mutations in the HFE gene and characterized by systemic iron overload in many tissues, including liver, heart, kidney, brain, and bone. Iron is essential metal ions in the human body and plays important physiological and biological roles in oxygen transport, DNA synthesize, energy metabolism, and hundreds of enzymes synthesize (Gozzelino and Arosio, 2016; Tang et al, 2018). Because its doubleedged sword effect in the body, iron homeostasis is delicately regulated. Cellular iron homeostasis is achieved by modulating the expression of proteins involved in iron uptake, storage, and export (Kuhn, 2015). Iron metabolism regulating proteins (IRPs) sense the concentration of active iron in the mitochondria and regulate the expression of iron uptake associated proteins transferrin receptor 1(TFR1) and divalent metal transporter 1 (DMT1) (Zhang et al, 2014). Disruption of iron homeostasis is reported to take parts in many diseases, such as Parkinson disease, Alzheimer disease, cardiovascular diseases and osteoporosis (Siddique and Kowdley, 2012)

Methods

Results

Conclusion