Molecular Mechanism of Ferroptosis in Orthopedic Diseases: Comparison
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Please note this is a comparison between Version 2 by Amina Yu and Version 1 by Xuchang Zhou.

Programmed Cell Death (PCD) is an active and orderly process of cell death, which plays an important role in the evolution of living organisms, the stability of the internal environment, and the development of multiple systems. PCD includes cell apoptosis, necrosis, pyroptosis, ferroptosis, and autophagy. Apoptosis is characterized by nuclear fragmentation, the formation of apoptotic bodies, and the activation of proteins such as pro-apoptotic B cell lymphoma-2 (BCL-2). It leads to the increase of mitochondrial outer membrane permeabilization (MOMP) and the production of reactive oxygen species (ROS), thereby releasing apoptotic factors and promoting cysteine cascade activation. During necrosis, the plasma membrane rupture, cytoplasmic organelle swelling, internucleosomal DNA fragmentation deficiency, ATP consumption, and damage-associated molecular patterns (DAMPs) release. When pyroptosis occurs, the plasma membrane ruptures, the inflammation-related active IL-1β and IL-18 are released, and the caspase-1 and gasdermin D (GSDMD) are activated by hydrolysis. Autophagy is characterized by the accumulation of autophagic vacuoles, cytoplasmic vacuolation, non-condensation of chromatin, the transformation of microtubule-associated protein light chain 3 (LC3)-I to LC3-II, and p62-cleaved.

  • ferroptosis
  • regulation of ferroptosis
  • bone marrow injury
  • osteoporosis
  • osteoarthritis

1. Bone Marrow Injury

Bone marrow is the hematopoietic tissue of the human body, in which red bone marrow can produce red blood cells, platelets, and various white blood cells. Platelets have hemostatic effect, and white blood cells can kill and inhibit various pathogens, including bacteria and viruses, and so etc.on [27][1]. At present, the regulation of various types of cell death in tumor cells is a popular target for new antitumor drugs under development [28,29][2][3]. Bone marrow injury is one of the most common dose-limiting side effects of such drugs, which may lead to neutropenia, thrombocytopenia or anemia, etc., thus further causing drug dose reduction, treatment time delay, and efficacy reduction in cancer treatment [22][4]. Studies have found that Fanconi anemia complementation group D2 (FANCD2), a nuclear protein involved in DNA damage repair, can inhibit damage in bone marrow stromal cells (BMSCs) with hematopoietic reconstitution and immune modulation caused by ferroptosis [22][4]. FANCD2 mono-ubiquitination is the most important step in the DNA cross-linking repair pathway. ThisIt studywas found that Erastin-induced ferroptosis significantly increased the level of mono-ubiquitinated FANCD2, thereby limiting DNA damage in BMSCs. In BMSCs with FANCD2 knockdown, Fe2+ and MDA levels increased, and GSH consumption increased. The mRNA expression of FTH1 (an inhibitor of ferroptosis by binding Fe2+ [30][5]) and STEAP3 (a metal reductase capable of converting Fe3+ to Fe2+) is inhibited. Similarly, the mRNA expression of GPX4 was downregulated, inducing the downregulation of the basic negative regulators of ferroptosis of HAMP [31][6] and HSPB1 [32][7] and increased DNA damage. In brief, FANCD2 reduces the side effects of anticancer drugs on bone marrow by regulating ferroptosis. Clinical studies have shown that bone marrow hematopoietic failure is the main cause of death in patients with Fanconi anemia (FA), a disease associated with one or more gene defects of 26 genes related to DNA double-strand break repair proteins [33,34,35][8][9][10]. When DNA is affected by radiation, chromosomes break and recombine, which leads to DNA breakage, and the FA protein repair mechanism is activated by the body. After 24 h of total body irradiation (TBI) of 8.5 Gy to bone marrow stromal cell lines of wild-type C57BL/6J mice, researchers injected the radiation alleviating drugs GS-nitroxide JP4-039 (anti-apoptosis), necrostatin-1 (anti-necrosis) and baicalein (anti-ferroptosis). The results showed that three drugs all improved the survival rate after radiation and had significant radioprotective effects, facilitated the repair of DNA damage, and thus slowed down bone marrow failure [36][11].

2. Osteoporosis

2.1. OP-Associated Osteoblasts with Ferroptosis

The existence of iron homeostasis is important for the normal physiological function of cells. Studies have found that OP is closely related to iron homeostasis, and intracellular iron homeostasis is mainly regulated by a variety of iron-related proteins, including intracellular ferritin, divalent metal transporters 1 (DMT1), and transferrin receptors (TfR) and transferrin (Tf) [43][12]. Iron overload is caused by the overexpression of DMT1 in osteoblasts, resulting in oxidative stress response and ultimately affecting the osteogenic function of osteoblasts, which plays an important role in the pathogenesis of T2DOP [44,45,46][13][14][15]. Ma et al. [23][16] and Wang et al. [47][17] both found that high glucose (HG) could affect the mitochondrial morphology of osteoblasts by increasing the density of the bilayer mitochondrial membrane and decreasing the mitochondrial cristae and that these changes in mitochondria morphology are consistent with ferroptosis characteristics. HG also changes osteogenic function-related indicators, including decreased expression of osteoprotegerin (OPG) and osteocalcin (OCN), decreased activity of alkaline phosphatase (ALP), and reduced the formation of mineralized nodules [23,47][16][17]. In addition, HG can also increase the intracellular ROS content, promote the accumulation of LPO, and reduce the expression level of ferroptosis-related protein GPX4 in cells, leading to ferroptosis and osteogenic function decline in osteoblasts. Previous studies have confirmed that nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) signaling pathways are directly downstream of ROS. It is involved in the regulation of the transcription of antioxidant-responsive element (ARE)-dependent genes to balance oxidative mediators and maintain cellular redox homeostasis [48][18] and is therefore also considered to be an important regulator of ferroptosis [49,50][19][20]. It was found that endogenous antioxidant Melatonin (N-acetyl-5-methoxytryptamine) reduced the levels of LPO and ROS in MC3T3-E1 cells exposed to HG (25.5 mM) by activating the Nrf2/HO-1 signaling pathway, increased activity of GPX4 and SLC7A11, and inhibited HG-induced ferroptosis. This, in turn, enhanced osteogenic ability, promoting trabecular bone formation, increasing bone mineral density (BMD) and bone volume relative to total tissue volume (BV/TV) and trabecular number (Tb.N), and improving bone microstructure. Knockdown of Nrf2 by siRNA inhibited the beneficial effect of melatonin on osteoblast activity. Further studies showed that the Nrf2 signaling pathway played a critical role in the intervention of melatonin on OP [23][16]. It has also been found that one of the most common causes of surgical failure and revision in total hip arthroplasty (THA) is aseptic loosening (AL). AL may be caused by particles induced osteolysis (PIO) released from the implant surface, leading to programmed death of MC3T3-E1 osteoblasts. CoCrMo radionuclides (CoNPs) promote the ferroptosis of osteoblasts by down-regulating the NRF2-ARE signaling pathway and inducing peri-implant PIO. Therefore, the blockade of ferroptosis with ferrostatin-1 and Nrf2 activator Oltipraz significantly improves PIO induced by the implantation of particles, which provides a potential strategy for treating AL [51][21]. Mitochondrial ferritin (FtMt) is a protein that stores iron ions and has ferroxidase activity. It can reduce the amount of free Fe2+ in mitochondria and prevent excessive Fe2+ from occurring Fenton reaction, thereby reducing the content of ROS [52][22]. Wang et al. [47][17] found that under HG conditions, the increased expression of mitochondrial DMT1 in hFOB1.19 osteoblasts leads to iron overload, and the overexpression of FtMt can reduce the intracellular ROS level and inhibit ferroptosis in osteoblasts. However, the silenced FtMt induced the mitochondrial phagocytosis through ROS/PINK1/Parkin pathway, which promoted the ferroptosis of osteoblasts and accelerated the pathological process of OP.

2.2. OP-Associated Osteoclasts with Ferroptosis

Ferritin (FTH) is a protein that stores excess cellular iron and may be degraded when cells are in an iron-deficient state, called “ferritin autophagy,” which will increase the sensitivity to ferroptosis caused by intracellular Fe2+ [53][23]. Osteoclasts, as acid-secreting cells and resorptive bone cells, contain abundant mitochondria to maintain high energy demand [54][24]. Therefore, mature osteoclasts require more intracellular free iron than other osteocytes [55][25]. Studies have found that ferritin autophagy is a process initiated by the degradation of ferritin heavy chain-nuclear receptor Coactivator 4 (FTH-NCOA4) complex autophagosome. It is activated by the receptor activator of nuclear factor Kappa B ligand (RANKL) under normoxic conditions. The occurrence of an iron deficiency response (increased TfR 1, decreased FTH) significantly increased MDA, and Fe2+ content decreased GSH level and induced osteoclast ferroptosis. In contrast, hypoxia-inducible factor 1 alpha (HIF-1α) can reduce RANKL-induced ferritin autophagy and autophagy flux under hypoxia and protect osteoclasts from ferroptosis. In vivo studies further showed that 2-methoxyestradiol (2ME2), the HIF-1α specific inhibitor, prevented bone loss in ovariectomized (OVX) mice [56][26]. Studies have also found that Artemisinin (ARS) and its related compounds are not only being used clinically as antimalarial drugs but also as a potential alternative drug in the treatment of bone loss. The possible mechanism is that ARS compounds significantly increase TFR1-mediated iron uptake during osteoclast differentiation. In the acidic endosome, Fe3+ is reduced to Fe2+, which is released into the cytoplasm as the liable iron pool (LIP) through DMT1. In addition, ARS compounds selectively inhibit osteoclast differentiation by downregulation of pathways involved in RANKL-induced osteoclastogenesis, resulting in the ferroptosis of osteoclasts [57][27].

3. Osteoarthritis

Osteoarthritis (OA) is a common chronic degenerative joint disease affected by multiple factors such as heredity, age, gender, trauma, and biomechanical abnormalities [58,59][28][29]. It is mainly characterized by cartilage degeneration, synovial inflammation, and subchondral bone remodeling [60,61][30][31]. Articular cartilage, which is composed of chondrocytes, is essential for maintaining the integrity of the extracellular matrix [62][32] and balancing articular cartilage homeostasis to slow the progression of OA [63][33]. Current pharmacological treatment strategies for OA mainly focus on relieving clinical pain symptoms, improving joint function, and improving bone mass but usually do not prevent disease progression [64][34]. Recent studies have found that chondrocyte ferroptosis is one of the causes of the progressive reduction of articular chondrocytes during OA progression. Yao et al. [64][34] used Interleukin-1 Beta (IL-1β) to simulate the inflammatory response and used ferric ammonium citrate (FAC) to simulate in vitro iron overload. These two measures all induced changes in ROS, lipid ROS accumulation, and ferroptosis-related protein expression in chondrocytes. It is manifested as promoting the expression of matrix metalloproteinase13 (MMP13) and inhibiting the expression of type II collagen (collagen II) in chondrocytes. It then disrupted the homeostasis of the chondrocyte matrix. Ferrostatin-1 is a ferroptosis-specific inhibitor that attenuates the ferroptosis-related ROS and protein expression changes induced by IL-1β and FAC, promoting the activation of the Nrf2 antioxidant system. In addition,  this study used a surgically induced mouse model of destabilized medial meniscus (DMM) was used to induce OA in vivo. In addition, an intra-articular injection of Ferrostatin-1 rescued the expression of collagen II and GPX4 in the mouse OA model, inhibited the occurrence of ferroptosis in chondrocytes, and reduced cartilage degradation and OA progression. Hypoxia-inducible factor 2 alpha (HIF-2α) has been reported to play an essential role in cartilage development, OA progression, and sensitizing cells to ferroptosis [65,66,67][35][36][37]. There were in vitro studies using IL-1β to treat chondrocytes in the OA microenvironment. The result showed that, with the IL-1β stimulation, the HIF-2α and LPO levels were upregulated in the chondrocytes, and the GSH level was downregulated. However, upon treatment with D-mannose, a C-2 epimer of glucose, the changes in the LPO and GSH levels can be reversed. At the same time, the level of malondialdehyde (MDA), a byproduct of LPO, was also correspondingly reduced. It also elevated the RNA and protein levels of two key ferroptosis repressors, GPX4 and SLC7A11. Thus, it reduced the sensitivity of chondrocytes to ferroptosis [24][38]. In studies of in vivo anterior cruciate ligament transection (ACLT) -induced OA mouse models, D-mannose delayed the progression of OA in mice by inhibiting HIF-2α-mediated chondrocyte sensitivity to ferroptosis [24][38]. Moreover, during OA, the synovium develops interstitial vascularization, fibrosis, and hyperplasia, leading to synovitis [68][39], which is closely associated with joint dysfunction, injury, and pain. These factors also lead to cartilage degeneration in OA [69][40]. It has been found that Icariin (ICA) suppresses the effect of ferroptosis activator RSL3 on cell viability, LPO, iron content, and related protein expression in synovial cells, thus protecting LPS-induced synoviocytes from ferroptosis [70][41]. Therefore, this study provides a new strategy is provided for the treatment of synovitis.

4. Osteosarcoma

Osteosarcoma (OS) is the most common primary malignant bone tumor [71,72][42][43], in adolescents, with a highly aggressive and distal metastatic [73][44]. However, conventional adjuvant chemotherapy regimens have reached a bottleneck. Cisplatin is a common chemotherapeutic agent for treating osteosarcoma, causing relatively few side effects. Nevertheless, OS patients often develop cisplatin resistance after long-term use, leading to treatment failure [74][45]. Therefore, inhibition of resistance to cisplatin in OS patients yields better therapeutic effects. The signal transducer and activator of transcription 3 (STAT3) belongs to the STAT family and is an important transcription factor involved in inflammation and tumor progression [75][46]. Nrf2 is a transcription factor that regulates the expression of various antioxidant proteins. STAT3 enhances the antioxidant capacity of cells by activating Nrf2, thus protecting cells from oxidative damage [76][47]. Studies of incubating OS cells (MG63 and Saos2) with increased doses of cisplatin have produced human osteosarcoma cells with cisplatin-resistant cells MG63/DDP and Saos2/DDP with increased viability and decreased mortality. It was also accompanied by decreased pSTAT3, Nrf2, and GPX4 protein levels and increased ROS, LPO, and MDA levels, causing ferroptosis and increased sensitivity to cisplatin [77][48]. Thus, long-term cisplatin induced the production of resistant osteosarcoma cells by inhibiting ferroptosis. STAT3/Nrf2/GPX4 signaling plays an important role in the drug resistance process of OS cells, which may be a potential therapeutic target to overcome cisplatin resistance in OS cells. Flavonoids have multiple biological functions, especially the anticancer effect induced by pro-oxidative activity [78][49]. Bavachin, a flavonoid, which Luo et al. [79][50] found to alter mitochondrial morphology in OS cells, resulting in smaller mitochondria, increased mitochondrial membrane density, and decreased mitochondrial cristae. Further studies revealed that Bavachin could upregulate the expression of transferrin receptors, such as DMT1 and P53, and downregulate the expression of ferritin light chain, ferritin heavy chain, p-STAT3, SLC7A11, and GPX4 in OS cells. Among these, P53 acts as an upstream mediator of SLC7A11, thus initiating ferroptosis in tumor cells [80][51]. More importantly, STAT3 overexpression, SLC7A11 overexpression, and pretreatment with pifithrin-α (P53 inhibitor) rescued Bavachin-induced ferroptosis in OS cells. In a word, the results indicate that Bavachin induces ferroptosis in OS cells by inhibiting the STAT3/P53/SLC7A11 axis [79][50]. The Mitogen-activated protein kinases (MAPK) pathway plays a crucial role in the signal transduction process of eukaryotic cells [81][52], as a key pathway in the OS-related mechanism, and helps to balance the relationship between tumor cell viability and mortality [82][53]. Phenethyl isothiocyanate (PEITC) can induce tumor cell cycle arrest and apoptotic [83][54]. Studies have found that PEITC can reduce the viability of human OS cells, inhibit cell proliferation, cause G2/M cell cycle arrest, alter iron metabolism, induce GSH depletion, generate ROS, activate the MAPK signaling pathway, and trigger ferroptosis in OS cells. Furthermore, PEITC with a dose of 30 mg/kg also significantly delayed tumor growth in the transplanted OS mouse model [25][55]. Tirapazamine (TPZ) is a hypoxic prodrug with antitumor effects in the tumor hypoxic microenvironment [84][56]. Shi et al. [85][57] demonstrated for the first time that TPZ induced ferroptosis in OS cells by inhibiting the expression of SLC7A11 under hypoxia conditions, thus preventing the proliferation and migration of osteosarcoma cells. EF24, a synthetic analog of curcumin, acts as an antitumor compound that induces apoptosis and inhibits proliferation and metastasis [86,87,88][58][59][60]. It has been shown that EF24 inhibited GPX4 expression and induced OS cells by increasing MDA levels, ROS levels, and intracellular iron ion levels, upregulating the expression of the cytoprotective enzyme heme oxygenase 1 (heme oxygenase 1, HMOX1), and induced ferroptosis in OS cells [89][61]. Therefore, EF24 may serve as a potential therapeutic agent for patients with HMOX1-positive OS.

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