The detrimental effect of iron on OA chondrocytes: Importance of pro‐inflammatory cytokines induced iron influx and oxidative stress

Abstract

Iron overload is common in elderly people which is implicated in the disease progression of osteoarthritis (OA), however, how iron homeostasis is regulated during the onset and progression of OA and how it contributes to the pathological transition of articular chondrocytes remain unknown. In the present study, we developed an in vitro approach to investigate the roles of iron homeostasis and iron overload mediated oxidative stress in chondrocytes under an inflammatory environment. We found that pro‐inflammatory cytokines could disrupt chondrocytes iron homeostasis via upregulating iron influx transporter TfR1 and downregulating iron efflux transporter FPN, thus leading to chondrocytes iron overload. Iron overload would promote the expression of chondrocytes catabolic markers, MMP3 and MMP13 expression. In addition, we found that oxidative stress and mitochondrial dysfunction played important roles in iron overload‐induced cartilage degeneration, reducing iron concentration using iron chelator or antioxidant drugs could inhibit iron overload‐induced OA‐related catabolic markers and mitochondrial dysfunction. Our results suggest that pro‐inflammatory cytokines could disrupt chondrocytes iron homeostasis and promote iron influx, iron overload‐induced oxidative stress and mitochondrial dysfunction play important roles in iron overload‐induced cartilage degeneration.

Interplay Between Iron Overload and Osteoarthritis: Clinical Significance and Cellular Mechanisms

“…Another study by Jing et al revealed that excess iron-mediated mitochondrial dysfunction in chondrocytes had a close association with oxidative stress. The association was established via the process of ROS generation, which in turn promoted the expression of OA-related catabolic markers (Jing et al, 2021a). The iron chelation method further confirmed the vital role of iron in chondrocyte dysfunction.…”

“…Multiple independent clinical studies have been conducted, and the results have indicated that elderly patients with high ferritin content have a four-fold increased risk of suffering from OA than patients with low ferritin content in their bodies. It has also been observed that the ferritin content has a positive association with the severity of joint through imaging analyses (Park et al, 2012;Jing et al, 2021a;Ke et al, 2021). Moreover, studies indicated that the incidence of high iron storage was higher in the elderly compared with populations of other ages, and this transition was more pronounced in older women than in men (Chen et al, 2015).…”

“…The effectiveness of iron chelators (such as DFO, deferiprone, and deferasirox) has been widely validated in iron overload diseases in patients requiring long-term transfusions and suffering from HH, SCD, and thalassemia (Borgna-Pignatti et al, 1998;Lal et al, 2013;Ballas et al, 2018). Although the pathogenesis of OA in patients with iron overload has not been fully explained, the adverse effects of iron overload on cells present in the joint and the progression of OA has been extensively reported (Depierreux et al, 1988;Barg et al, 2011;Jing et al, 2021a). Therefore, the process of iron chelation therapy can be potentially used to shed light on the process of the prevention or treatment of iron overload-related OA.…”

The Impact of Trace Elements on Osteoarthritis

“…Excessive iron also can produce reactive oxygen species through Fenton or Haber Weiss reaction, resulting in oxidative stress ( 69 ). This will over activate matrix metalloproteinases that degrade extracellular matrix, thereby reducing the resistance of cartilage to mechanical stress and exacerbating OA ( 70 ).…”

“…Cartilage degeneration brought with reduced expression of transcripts for aggrecan and type II collagen in iron overload animals ( 112 ). The cartilage injury caused by systemic iron overload is also related to the increased transcriptional counts of pro-inflammatory cytokines such as interleukin-1β and tumor necrosis factor-α in the cartilage and infrapatellar fat pad ( 70 ). Iron overload can destroy the metabolism of chondrocytes and promote the establishment of an OA-related phenotype ( 112 ).…”