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

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.

Calcium chelator BAPTA‑AM protects against iron overload‑induced chondrocyte mitochondrial dysfunction and cartilage degeneration

“…The present study demonstrated that iron reduced cell viability and increased chondrocyte apoptotic rate, which was also reversed by calcium chelator treatment. Our previous study demonstrated that pro-inflammatory cytokines could disrupt iron homeostasis and promote iron influx via promoting the expression of the iron influx regulators TfR1 and DMT1 (26). In the present study, it was observed that the pro-inflammatory cytokine IL-1β promoted mitochondrial fission protein and MMP expression, which was induced by iron overload.…”

“…MMPs. Our previous findings demonstrated the association between iron overload and OA progression (26). In the present study, it was investigated whether calcium chelator treatment could protect chondrocytes against iron overload-induced apoptosis and suppress the expression of MMPs.…”

“…Our previous studies have demonstrated the detrimental effect of iron on osteoarthritis (OA) chondrocytes (1), and that arresting iron influx or decreasing iron concentration using iron chelators may inhibit iron deposition-induced OA progression (2). Iron chelators are drugs that may be beneficial for patients with iron overload (3).…”

D‐mannose alleviates osteoarthritis progression by inhibiting chondrocyte ferroptosis in a HIF‐2α‐dependent manner

“… 9 Iron‐overloaded mice exhibit increased cartilage destruction, and intracellular iron uptake is favoured in chondrocytes mimicking an OA phenotype. 10 , 11 These findings suggest that ferroptosis suppression is a novel candidate component for preventing OA progression.…”

“…9 Iron-overloaded mice exhibit increased cartilage destruction, and intracellular iron uptake is favoured in chondrocytes mimicking an OA phenotype. 10,11 These findings suggest that ferroptosis suppression is a novel candidate component for preventing OA progression. D-mannose, a C-2 epimer of glucose, is naturally present in many fruits and plants, and has been reported to be beneficial in many human disease states.…”