Deferoxamine Alleviates Osteoarthritis by Inhibiting Chondrocyte Ferroptosis and Activating the Nrf2 Pathway

Abstract

Objective: Osteoarthritis (OA) is a common disease with a complex pathology including mechanical load, inflammation, and metabolic factors. Chondrocyte ferroptosis contributes to OA progression. Because iron deposition is a major pathological event in ferroptosis, deferoxamine (DFO), an effective iron chelator, has been used to inhibit ferroptosis in various degenerative disease models. Nevertheless, its OA treatment efficacy remains unknown. We aimed to determine whether DFO alleviates chondrocyte ferroptosis and its effect on OA and to explore its possible mechanism.Methods: Interleukin-1β (IL-1β) was used to simulate inflammation, and chondrocyte ferroptosis was induced by erastin, a classic ferroptosis inducer. A surgical destabilized medial meniscus mouse model was also applied to simulate OA in vivo, and erastin was injected into the articular cavity to induce mouse knee chondrocyte ferroptosis. We determined the effects of DFO on ferroptosis and injury-related events: chondrocyte inflammation, extracellular matrix degradation, oxidative stress, and articular cartilage degradation.Results: IL-1β increased the levels of ROS, lipid ROS, and the lipid peroxidation end product malondialdehyde (MDA) and altered ferroptosis-related protein expression in chondrocytes. Moreover, ferrostatin-1 (Fer-1), a classic ferroptosis inhibitor, rescued the IL-1β–induced decrease in collagen type II (collagen II) expression and increase in matrix metalloproteinase 13 (MMP13) expression. Erastin promoted MMP13 expression in chondrocytes but inhibited collagen II expression. DFO alleviated IL-1β– and erastin-induced cytotoxicity in chondrocytes, abrogated ROS and lipid ROS accumulation and the increase in MDA, improved OA-like changes in chondrocytes, and promoted nuclear factor E2–related factor 2 (Nrf2) antioxidant system activation. Finally, intra-articular injection of DFO enhanced collagen II expression in OA model mice, inhibited erastin-induced articular chondrocyte death, and delayed articular cartilage degradation and OA progression.Conclusion: Our research confirms that ferroptosis occurs in chondrocytes under inflammatory conditions, and inhibition of chondrocyte ferroptosis can alleviate chondrocyte destruction. Erastin-induced chondrocyte ferroptosis can stimulate increased MMP13 expression and decreased collagen II expression in chondrocytes. DFO can suppress chondrocyte ferroptosis and promote activation of the Nrf2 antioxidant system, which is essential for protecting chondrocytes. In addition, ferroptosis inhibition by DFO injection into the articular cavity may be a new OA treatment.

Metformin alleviates osteoarthritis in mice by inhibiting chondrocyte ferroptosis and improving subchondral osteosclerosis and angiogenesis

“…Briefly, after mice were anesthetized with an intraperitoneal injection of 1% sodium pentobarbital (60 mg/kg) [ 37 ], the meniscotibial ligament of the right knee was transected to free the anterior crus of the meniscus, and sham surgery was performed without transecting the meniscotibial ligament. Mice were injected intra-articularly with Erastin (15 mg/kg) [ 38 ], and the sham and DMM groups were injected with an equal volume of saline twice a week. Moreover, Met was administered by gavage (200 mg/kg/day) [ 23 ].…”

Emerging Roles of the Iron Chelators in Inflammation

“…DFO and DFP anti-inflammatory properties have been investigated in several inflammatory conditions. Recently, it has been demonstrated the capability of DFO to modulate inflammation in a common inflammatory disease, osteoarthritis (OA) by reducing chondrocyte inflammation and matrix destruction both in vitro and in vivo [ 73 ]. A specific relationship between chondrocyte ferroptosis and OA has been proposed.…”

The Regulatory Role of Ferroptosis in Bone Homeostasis

“…Studies have also been conducted to identify a feasible treatment for chondrocyte degeneration with a focus on cell ferroptosis [ 72 ]. Deferoxamine (DFO) [ 73 ] and D-mannose were recently demonstrated to alleviate OA progression by inhibiting of chondrocyte ferroptosis. DFO was found to both effectively ameliorate chondrocyte ferroptosis and induce activation of the Nrf2 antioxidant system, which is crucial for chondrocyte protection [ 73 ].…”

“…Deferoxamine (DFO) [ 73 ] and D-mannose were recently demonstrated to alleviate OA progression by inhibiting of chondrocyte ferroptosis. DFO was found to both effectively ameliorate chondrocyte ferroptosis and induce activation of the Nrf2 antioxidant system, which is crucial for chondrocyte protection [ 73 ]. The efficacy of injection of DFO in OA mice was also demonstrated in vivo [ 73 ].…”

“…DFO was found to both effectively ameliorate chondrocyte ferroptosis and induce activation of the Nrf2 antioxidant system, which is crucial for chondrocyte protection [ 73 ]. The efficacy of injection of DFO in OA mice was also demonstrated in vivo [ 73 ]. Similarly, Zhou et al [ 74 ] investigated whether D-mannose mediates chondrocyte ferroptosis during OA cartilage degeneration in vitro and in vivo .…”