CoCrMo‐Nanoparticles induced peri‐implant osteolysis by promoting osteoblast ferroptosis via regulating Nrf2‐ARE signalling pathway

Abstract

Objectives Aseptic loosening (AL) is the most common reason of total hip arthroplasty (THA) failure and revision surgery. Osteolysis, caused by wear particles released from implant surfaces, has a vital role in AL. Although previous studies suggest that wear particles always lead to osteoblast programmed death in the process of AL, the specific mechanism remains incompletely understood and osteoblast ferroptosis maybe a new mechanism of AL. Materials and Methods CoCrMo nanoparticles (CoNPs) were prepared to investigate the influence of ferroptosis in osteoblasts and calvaria resorption animal models. Periprosthetic osteolytic bone tissue was collected from patients who underwent AL after THA to verify osteoblast ferroptosis. Results Our study demonstrated that CoNPs induced significant ferroptosis in osteoblasts and particles induced osteolysis (PIO) animal models. Blocking ferroptosis with specific inhibitor Ferrostatin‐1 dramatically reduced particle‐induced ferroptosis in vitro. Moreover, in osteoblasts, CoNPs significantly downregulated the expression of Nrf2 (nuclear factor erythroid 2‐related factor 2), a core element in the antioxidant response. The overexpression of Nrf2 by siKeap1 or Nrf2 activator Oltipraz obviously upregulated antioxidant response elements (AREs) and suppressed ferroptosis in osteoblasts. Furthermore, in PIO animal models, the combined utilization of Ferrostatin‐1 and Oltipraz dramatically ameliorated ferroptosis and the severity of osteolysis. Conclusions These results indicate that CoNPs promote osteoblast ferroptosis by regulating the Nrf2‐ARE signalling pathway, which suggests a new mechanism underlying PIO and represents a potential therapeutic approach for AL.

ALDH3B1 protects interfollicular epidermal cells against lipid peroxidation via the NRF2 pathway

“…we selected the iron death inducers Rsl3 and erastin to culture IFE cells. We observed that the ALDH3B1 group had higher cell viability and lower levels of lipid peroxidation than the control group.In addition, it has been reported that the NRF2 pathway plays a key role in the body's resistance to lipid peroxidation, and this pathway can reduce oxidative damage and is involved in the regulation of antioxidant gene expression during oxidative stress, thereby enhancing cellular resistance to lipid peroxidation (34)(35)(36)(37). We therefore hypothesized that activation of the NRF2 pathway elevates the expression of ALDH3B1 and thus promotes the resistance of IFE cells to lipid peroxidation damage.…”

GSK-3β suppression upregulates Gli1 to alleviate osteogenesis inhibition in titanium nanoparticle-induced osteolysis

“…Recently, nanosized wear particles below 0.1 μm were found both in joint simulators and periprosthetic tissues [ 46 , 47 ]. More and more studies revealed the key role of wear nanoparticles in osteolysis diseases [ 48 , 49 ]. Studies also demonstrated that titanium nanoparticles do not only influence MSCs enzymes activity but also contribute to cytotoxic and genotoxic effects [ 50 – 52 ].…”

Emerging Potential Therapeutic Targets of Ferroptosis in Skeletal Diseases

“…The activity of Fer-1 is determined by the primary aromatic amine, which particularly suppresses lipid oxidation and decreases the accumulation of ROS [ 1 ]. In addition, Fer-1 can inhibit osteoblast ferroptosis by regulating the Nrf2-ARE signaling pathway, thereby alleviating nanoparticle-induced peri-implant osteolysis [ 53 ]. In comparison with Fer-1, new-generation ferrostatins (SRS 11–92 and SRS 16–86) have the advantages of improving the stability of metabolism and tremendously preventing diseases such as acute kidney injury and ischemia-reperfusion injury [ 54 , 55 ].…”