Mechanisms of Ferroptosis in Intervertebral Disc Degeneration Therapy: History
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Contributor:
Jiaxing Chen
,
Xinyu Yang
,
Yi Feng
,
Qiaochu Li
,
Jingjin Ma
,
Linbang Wang
,
Zhengxue Quan

Intervertebral disc degeneration (IVDD) is a common pathological condition responsible for lower back pain, which can significantly increase economic and social burdens. Although considerable efforts have been made to identify potential mechanisms of disc degeneration, the treatment of IVDD is not satisfactory. Ferroptosis, a recently reported form of regulated cell death (RCD), is characterized by iron-dependent lipid peroxidation and has been demonstrated to be responsible for a variety of degenerative diseases. Accumulating evidence suggests that ferroptosis is implicated in IVDD by decreasing viability and increasing extracellular matrix degradation of nucleus pulposus cells, annulus fibrosus cells, or endplate chondrocytes.

  • intervertebral disc degeneration
  • ferroptosis
  • iron
  • lipid peroxidation

1. Iron Overload

1.1. Iron

Iron is an essential microelement to maintain the function of iron-containing proteins, which are involved in various pathophysiological processes, such as catalyzing the formation of hydroxyl radicals, inducing cell death, and regulating DNA replication [1]. Ferrous iron (Fe2+) and ferric iron (Fe3+) are the main states of iron in mammalian cells, and Fe2+ can be converted to Fe3+ through the Fenton reaction to generate excessive ROS, which triggers oxidative stress and ferroptosis [2]. Transferrin receptor 1 (TfR1), TfR2, and divalentmetal transporter 1 (DMT1) are all responsible for taking extracellular iron into the cytoplasm, and the excess cellular iron is either stored in the ferritin heavy chain (FTH) or exported by ferroportin (FPN) [3]. The mechanisms of maintaining cellular iron homeostasis are so complex that problems in any of these iron transfer pathways are likely to disturb the balance, leading to the occurrence and progression of diseases.
The role of iron overload in disc degeneration remains controversial in the literature. Wang et al. revealed that patients with severe IVDD had a higher serum ferritin level than patients with non-severe IVDD. He established an iron-overloading mouse model and demonstrated that iron overload could promote endplate chondrocyte calcification and degeneration in a ferroptosis-related manner [4]. On the other hand, Zhang et al. found that iron deficiency of human NP cells could significantly influence the synthesis and function of iron-containing proteins, such as DNA polymerase epsilon complex (PolE), eventually leading to apoptosis of NP cells [5]. Guo et al. concluded that serum iron was negatively correlated with the degree of IVDD by a clinical study [6]. Nevertheless, Aessopos et al. suggested that the serum ferritin concentration was not responsible for intervertebral disc calcification in patients with thalassemia intermedia [7]. Notably, cellular iron homeostasis is important for the normal physiological functions of the body, and both iron overload and deficiency can have disastrous consequences for intervertebral disc cells.

1.2. Ferritinophagy

Nuclear receptor coactivator 4 (NCOA4), a selective receptor, can specifically bind FTH and disturb intracellular iron homeostasis in a ferritinophagy manner [8]. Excessive ferritinophagy could lead to labile iron overloading [9]. Yang et al. demonstrated that oxidative stress and ferroptosis induced by tert-butyl hydroperoxide (TBHP) could decrease the proliferation and vitality of rat NP cells and AF cells. Then, they elaborated the mechanism of ferroptosis-related pathways in rat NP cells and AF cells: upregulated NCOA4 combines with FTH1 and significantly enhances ferritin degradation, increasing the concentration of cellular Fe2+; excessive ROS generation by the Fenton reaction ultimately leads to lipid peroxidation of the cell membrane and ferroptosis [10]. Autophagy flow of the intervertebral disc cells was somehow enhanced by TBHP, but the authors did not discuss the specific regulation mechanisms for such enhancing [10]. Previous studies have shown that ROS-related oxidative stress can trigger autophagy in rat NP cells through the MAPK pathway and can upregulate matrix metalloproteinase-3 (MMP-3) in AF cells [11][12]. Autophagy is correlated with ferroptosis in a harmonious way, and such correlation warrants further investigation in intervertebral disc cells to define potential therapeutic biomarkers for IVDD.

1.3. Iron Exportation

FPN, a multi-transmembrane protein, is the only reported transporter in mammals to export excessive intracellular ferrous iron and is mainly responsible for maintaining cellular iron homeostasis [13]. FPN deficiency can lead to labile iron accumulation in breast cancer cells, and ferrous iron-related ROS production (Fenton reaction) eventually contributes to ferroptosis [14]. Metal-regulatory transcription factor 1 (MTF1) can bind to the gene promoters to regulate the expression of target genes, which largely depends on its translocation from the cytoplasm to the nucleus [15][16]. Lu et al. elucidated that the FPN dysfunction induced by TBHP was significantly associated with intracellular iron overload and ferroptosis in human NP cells [17]. The underlying mechanism of downregulated FPN is c-jun N-terminal kinase (JNK) activation, which can attenuate the nuclear translocation of MTF1. Hinokitiol could restore the FPN function to suppress ferroptosis of NP cells in vitro and to ameliorate IVDD in vivo [17]. JNK/MTF1/FPN can act as a ferroptosis-related pathway in intervertebral disc cells and can serve as a novel therapeutic target against IVDD.

1.4. Neovascularization

The intervertebral disc is accepted as an avascular tissue, and the cartilage endplate provides most of its nutrition [18]. As early as the 1990s, neovascularization in herniated NP tissues was observed by some researchers [19]. Arai et al. observed vascularized granulation tissues along the tears in the extruded tissues during degenerative disc herniation [20]. Oxidation of hemoglobin followed by the formation of heme moieties (ferriporphyrin) could induce cell death by iron-related oxidative damage [21]. Shan et al. clarified that heme that extravasated from neovascularization could contribute to iron accumulation and ferroptosis in human NP cells and tissues by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) [22]. In fact, previous literature demonstrated that neovascularization plays an important role in promoting IVDD [23][24]. Thus, neovascularization-induced ferroptosis could act as a promising target for IVDD treatment, and the inhibition mechanisms of neovascularization in IVDD warrant further investigation.

2. Inflammation

Inflammation has been a hallmark of various diseases, and the pathogenesis of these diseases is associated with some pro-inflammatory cytokines, such as interleukin 6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) [25][26]. IL-6 can mediate the expression of GPX4 through modulating the STAT3/GPX4 signaling pathway in cardiac microvascular endothelial cells [26], and GPX4 is significantly associated with ferroptosis. In addition, both clinical and basic research demonstrated that inflammation was responsible for IVDD, but research regarding the relationship between pro-inflammatory cytokines and ferroptosis in IVDD is lacking [27][28][29]. Sheng et al. demonstrated that IL-6 could induce iron overload, lipid peroxidation, and ferroptosis in cartilage cells of human intervertebral discs [30]. The level of GPX4 was significantly reduced in the degenerative cartilages compared with normal tissues, and overexpression of miR-10a-5p could alleviate IL-6 receptor-induced cartilage ferroptosis [30]. Consequently, regulating pro-inflammatory factor receptors at the post-transcriptional level to alleviate ferroptosis in intervertebral disc cells may be a promising way to treat IVDD. Not only micro RNA, but methylation or some other epigenetic modifications are also worthy of study.

3. Inhibition Mechanisms

3.1. GPX4

Redox balance is critical to ensure normal physiological function of cells and tissues, and GPX4 is regarded as the main component of the antiperoxidative defense to maintain redox balance [31]. In combination with GSH, GPX4 alleviates the lipid peroxidation of the cell membrane by expending intracellular peroxidation substances [32]. Previous studies have proved that downregulated GPX4 would make cells more sensitive to ferroptosis, while upregulated GPX4 would decrease the sensitivity of cells to ferroptosis [33]. Homocysteine (Hcy) is the mediate product in the methionine cycle and can be converted back to methionine with the involvement of 5-methyltetrahydrofolate, and methyl transfer happens in this metabolic cycle [34]. Hcy can also be converted to cysteine through the trans-sulfuration pathway, which is one of the main sources of GSH synthesis [35]. Intracellular Hcy metabolic disorders could contribute to cell dysfunction and even cell death. Inhibition of cystathionine β-synthase (CBS), a key enzyme in the trans-sulfuration pathway, and S-adenosyl homocysteine hydrolase (SAHH), a key enzyme in the methionine cycle, could trigger ferroptosis in cancer cells [35][36].
Zhang et al. verified that higher serum Hcy concentration was associated with IVDD by analyzing clinical data [37]. He also elucidated that excessive Hcy could aggravate ferroptosis and oxidative stress in NP cells of Sprague–Dawley rats. The upregulation of DNA methyltransferase, DNMT1, and DNMT3 induced by excessive Hcy could increase the methylation of GPX4 and downregulate its protein expression [37]. Recently, some researchers have proposed that an increased level of Hcy was not the cause of diseases but the consequence, and S-adenosylhomocysteine (SAH) might be the main pathogenesis [38]. In addition, when Hcy concentration increased in the medium of vascular smooth muscle cells, the intracellular levels of SAH, an inhibitor of methylation, were significantly increased [39].
The methionine metabolic cycle is implicated in IVDD with complex molecular mechanisms and regulatory networks, including methylation-related and ferroptosis-related pathways, warranting further experimental verification to help clinicians with the treatment of IVDD.

3.2. System Xc−

System Xc−, an amino acid antiporter, is composed of cystine transporter solute carrier family 7 member 11 (SLC7A11) [40]. SLC7A11 is involved in the synthesis of the major antioxidant GSH by importing cystine and upregulating cysteine [41]. Activation transcription factor 3 (ATF3) can specifically bind to the promotor of SLC7A11 to inhibit its expression, resulting in ferroptosis of cancer cells [42]. Li et al. revealed that TBHP could induce ATF3 overexpression and ferroptosis in human NP cells. ATF3 knockdown could downregulate IL-1β and upregulate SLC7A11 to suppress ferroptosis of NP cells in vitro and could alleviate the progression of IVDD in vivo [43]. miR-874-3p was elaborated to be the upstream regulator of ATF3 by binding to its target transcripts to downregulate ATF3. Notably, miRNA plays a pivotal role in mediating the expression of ferroptosis-related genes, such as System Xc− and IL-6 receptor, by post-transcriptional regulation and is the key target for future research regarding ferroptosis in IVDD.

3.3. NRF2

Nuclear factor E2-related factor 2 (NRF2) is a major regulator of antioxidant and cellular protective pathways, and both GSH-GPX4 and System Xc− are its downstream targets for maintaining redox balance in cells [44]. Harada et al. showed that NRF2 could regulate intracellular iron metabolism and was associated with oxidative stress and ferroptosis in macrophages [45]. Existing evidence has demonstrated that circular RNA, a non-coding RNA, can bind to micro RNA to regulate the expression of its target genes [46][47]. Yu et al. suggested that circ_0072464 in bone marrow mesenchymal stem cell (BMSC)-derived extracellular vesicles could increase NRF2 synthesis and alleviate ferroptosis in mouse NP cells by binding to miR-431 [48]. Encouragingly, Ukeba et al. demonstrated that BMSCs co-cultured with rabbit NP cells could increase the NP cell viability and upregulate ECM [49]. Stem cells provide a potential therapeutic target against IVDD, and the specific pathways of the stem cell involved in alleviating IVDD need further verification.

This entry is adapted from the peer-reviewed paper 10.3390/cells11213508

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