Chondrocyte ferroptosis contribute to the progression of osteoarthritis

Abstract

Summary Background Osteoarthritis (OA) is a complex process comprised of mechanical load, inflammation, and metabolic factors. It is still unknown that if chondrocytes undergo ferroptosis during OA and if ferroptosis contribute to the progression of OA. Materials and methods In our study, we use Interleukin-1 Beta (IL-1β) to simulate inflammation and ferric ammonium citrate (FAC) to simulate the iron overload in vitro . Also, we used the surgery-induced destabilized medial meniscus (DMM) mouse model to induce OA in vivo . We verify ferroptosis by its definition that defined by the Nomenclature Committee on Cell Death with both in vitro and in vivo model. Results We observed that both IL-1β and FAC induced reactive oxygen species (ROS), and lipid ROS accumulation and ferroptosis related protein expression changes in chondrocytes. Ferrostatin-1, a ferroptosis specific inhibitor, attenuated the cytotoxicity, ROS and lipid-ROS accumulation and ferroptosis related protein expression changes induced by IL-1β and FAC and facilitated the activation of Nrf2 antioxidant system. Moreover, erastin, the most classic inducer of ferroptosis, promoted matrix metalloproteinase 13 (MMP13) expression while inhibited type II collagen (collagen II) expression in chondrocytes. At last, we proved that intraarticular injection of ferrostatin-1 rescued the collagen II expression and attenuated the cartilage degradation and OA progression in mice OA model. Conclusions In summary, our study firstly proved that chondrocytes underwent ferroptosis under inflammation and iron overload condition. Induction of ferroptosis caused increased MMP13 expression and decreased collagen II expression in chondrocytes. Furthermore, inhibition of ferroptosis, by intraarticular injection of ferrostatin-1, in our case, seems to be a novel and promising option for the prevention of OA. The translational potential of this article The translation potential of this article is that we first indicated that chondrocyte ferroptosis contribute to the progression of osteoarthritis which provides a novel strategy in the prevention of OA.

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

“…Our findings in vitro prompted us to further analyse the function of HIF‐2α downregulation in D‐mannose‐induced chondrocyte resistance to ferroptosis and OA progression in vivo. Consistent with previous studies which indicated the role of chondrocyte ferroptosis in OA progression, 9 , 10 immunofluorescence staining described above revealed a striking reduction of the key ferroptosis inhibitor, GPX4, in the articular chondrocytes upon ACLT surgery (Figure 3A ). To examine whether D‐mannose‐induced inhibition of HIF‐2α would protect osteoarthritic cartilage by suppressing chondrocyte ferroptosis, we fed mice with D‐mannose solution or water as previously described and then performed ACLT surgery.…”

“…Recent evidence has indicated that chondrocyte ferroptosis contributes to chondrocyte homeostasis and osteoarthritic cartilage degeneration. 9 Similar to previous study, ferrostatin‐1 (Fer‐1), the inhibitor of ferroptosis, could attenuate the cytotoxicity of IL‐1β to chondrocytes, indicating the existence of ferroptosis in IL‐1β‐treated chondrocytes (Figure S2 A). GPX4 is a canonical glutathione‐based ferroptosis inhibitor and functions mainly through inhibiting the formation of lipid peroxides.…”

“…Earlier research reported several ferroptosis‐related features, such as abnormal iron metabolism, 10 , 11 , 37 , 38 lipid peroxidation 39 , 40 and mitochondrial dysfunction, 41 , 42 are closely correlated with accelerating cartilage destruction. It is only recently that Yao et al 9 first demonstrated that chondrocyte ferroptosis contributes to the progression of osteoarthritis. In fact, besides ferroptosis, other forms of cell death, including necrosis, apoptosis and autophagy, of chondrocytes all interplay with cartilage degradation and OA progression.…”

“…Recent evidence has indicated that chondrocyte ferroptosis contributes to the progression of OA. 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.…”

Iron Overload-Induced Ferroptosis Impairs Porcine Oocyte Maturation and Subsequent Embryonic Developmental Competence in vitro

“…In the present research, a highly selective inducer of iron overload, ferric ammonium citrate (FAC), was used to establish an iron overload model in porcine oocytes. FAC, a trivalent iron salt, is absorbed in vivo by reducing trivalent iron to divalent ferrous iron (Cotticelli et al, 2019;Yao et al, 2021). It has been shown that FAC-induced intracellular iron overload causes ferroptosis (Fang et al, 2018).…”