Ferroptosis in Arthritis: Driver of the Disease or Therapeutic Option?
<p>General overview of the mechanisms of ferroptosis, irrespective of the cell type. System Xc- functions as an amino acid antiporter, widely distributed within phospholipid bilayers. Comprising two subunits, solute carrier family 7 member 11 (SLC7A11) and solute carrier family 3 member 2 (SLC3A2), it forms a crucial part of the cellular antioxidant system. The exchange of cystine and glutamate occurs through System Xc- at a balanced ratio of 1:1, both entering and exiting the cell. Cystine, acquired through cellular uptake, undergoes reduction within cells and participates in glutathione (GSH) synthesis. GSH plays a role as an electron donor in reducing reactive oxygen species (ROS) and reactive nitrogen under the influence of GPXs, thereby forming oxidized GSSG out of two GSH molecules. Hampering the function of system Xc- influences the synthesis of GSH by impeding cystine absorption, leading to diminished GPX activity, reduced cellular antioxidant capacity, lipid ROS accumulation, and oxidative damage, culminating in ferroptosis. Further abbreviations are explained in the abbreviation table at the end of the review.</p> "> Figure 2
<p>Experiments on ferroptosis in rheumatoid arthritis. Animal experiments are marked in blue. Experiments on isolated human fibroblast-like synoviocytes (FLS) are marked in pink. Abbreviations are explained in the glossary.</p> "> Figure 3
<p>Experiments on ferroptosis in osteoarthritis. Animal experiments for inhibition or induction of ferroptosis in vivo or in vitro are marked in purple. Experiments on human chondrocytes in vitro are marked in green. Abbreviations are explained in the glossary.</p> ">
Abstract
:1. Introduction
1.1. Regulating Ferroptosis
1.2. Iron Metabolism
1.3. Lipid Peroxidation Pathways
2. Ferroptosis in Inflammatory Arthropathies
2.1. Ferroptosis in Resident Joint Cells: Fibroblast-Like Synoviocytes (FLSs) and Synovial Membrane
2.2. Ferroptosis in Innate Immune Cells
2.2.1. Polymorphonuclear Neutrophils (PMN)
2.2.2. Macrophages and Dendritic Cells (DC)
2.3. Ferroptosis in Adaptive Immune Cells
2.3.1. B Lymphocytes (B Cells)
2.3.2. T Lymphocytes (T Cells)
2.4. Rheumatoid Arthritis (RA)
2.4.1. Iron Metabolism in RA
2.4.2. Ferroptosis in RA
2.4.3. Ferroptosis Inducers in RA-FLS
2.4.4. Ferroptosis Inhibitors in RA-FLS
2.5. Spondylarthritis (SpA) and Other Arthritic Forms
2.5.1. Ferroptosis in Spondylarthritis
2.5.2. Ferroptosis in Psoriatic Arthritis
2.6. Ferroptosis in Crystal-Induced Arthritis
3. Ferroptosis in Osteoarthritis
3.1. Ferroptosis Inhibition in IL-1β Stimulated Chondrocytes
3.2. Ferroptosis Inhibition in Unstimulated Chondrocytes
4. Interpretation of the Data
5. Conclusions and Future Perspectives
Author Contributions
Funding
Conflicts of Interest
Abbreviations
Abbreviation | Name | Description |
4-HNE | 4-hydroxynonenal | Triggers inflammation |
γ-Ory | Gamma-oryzanol | Substance found in rice bran oil |
AA | Arachidonic acid | Type of omega-6 polyunsaturated fatty acid, primarily bound to ACSL4 through thioesterification process |
ACLT | Anterior cruciate ligament transection | Used to induce OA in animal models. |
ACO1 | Aconitase 1 | Cytosolic regulatory protein, monitors iron levels |
ACPA | Anti citrullinated protein antibodies | Sustains inflammation in RA; connection between presence of ACPA and development of bone erosions and pain in RA |
ACSF2 | Acyl-CoA synthetase family member 2 | Differentially expressed FRG |
ACSL4 | Acyl-CoA synthetase long-chain family member 4 | Takes part in biosynthesis and remodeling of PE, facilitating PUFA activation, influencing transmembrane characteristics of PUFAs |
AIF-M2 | Apoptosis-inducing factor—mitochondria-associated | A protein that suppresses ferroptosis |
Akt | Protein kinase B | A serin/threonine kinase |
ALOX12 | Arachidonate 12-lipoxygenase | Belongs to mammalian lipoxygenase family |
ARE | Antioxidant response elements | Is activated by Nrf2 |
ATF3 | Activating transcription factor 3 | Is a key ferroptosis-related gen |
AURKA | Serine/threonine-protein kinase 6 | Is a ferroptosis-related biomarker in OA |
AZ | Acetyl zingerone | Recently discovered antioxidant compound from curcumin |
BCA | Biochanin A | Newly discovered bioactive compound from Huangqi (a plant) |
BMPR2 | Bone morphogenetic protein receptor type 2 | An upregulated gene in PsA synovium |
BzATP | 2′(3′)-O-(4-Benzoylbenzoyl) adenosine 5-triphosphate | A ferroptosis agonist |
CA-074Me | CA-074-methyl ester | Can cause ferroptosis, cathepsin B inhibitor |
CAT | Capsiate | A metabolite produced by intestinal microorganisms |
CCR2 | C-C chemokine receptor type 2 | A chemokine receptor |
CDKN1A | Cyclin-dependent kinase inhibitor 1A | A ferroptosis-related gene |
CIA | Collagen-induced arthritis | Collagen-induced arthritis in a mouse model |
CISD1 | CDGSH iron sulfur domain 1 | A key ferroptosis regulator linked to PsA |
CLEC2B | C-type lectin domain family 2 member B | A hub gene in PsA |
COL2 | Collagen type II | Decreased in ferroptotic cells. |
COX2 | Cyclooxygenase 2 | Increased during ferroptosis as it is a ferroptosis regulator |
CTSB | Cathepsin B | A potential biomarker for RA, associated with ferroptosis |
CX43 | Connexin 43 | The target gene of miR-1 |
CXCL | Chemokine ligand | Chemokines; subfamily strongly linked with tumors and inflammatory conditions |
DEGs | Differentially expressed genes | Expression enriched in mitochondria-related pathways |
DMM | Destabilization of the medial meniscus | Animal models of OA established by DMM surgery |
DMT1 = SLC11A2 | Divalent metal transporter 1 | Facilitates transfer of Fe2+ from endosome to labile iron pool within cytoplasm |
Drp1 | Dynamin-related protein | Protein associated with the process of mitochondrial division |
EGFR | Epidermal growth factor receptor | Ferroptosis-related biomarker in OA |
EGR1 | Early growth response 1 | A ferroptosis-related gene |
ENO1 | Enolase 1 | A hub gene in ferroptosis |
ERK | Extracellular signal-regulated kinase | Serin/threonine kinase |
ES NS | Epigallocatechin-3-gallate-based nanodrugs | Reduce OA induced by ferroptosis |
Fer | Ferrostatin | Ferroptosis inhibitor |
FoxO | Forkhead box O | FoxO signal pathway important in ferroptosis |
FPN = SLC11A3 | Ferroportin | Protein for iron export |
FRG | Ferroptosis-related genes | Used to categorize AS into two subtypes |
FSP1 | Ferroptosis-suppressor-protein 1 | A protein that suppresses ferroptosis |
FTH | Ferritin heavy chain | Is used to create ferritin |
FTL | Ferritin light chain | Is used to create ferritin |
G1dP3 | Galectin-1-derived peptide | Anti-inflammatory and anti-proliferative properties in RA-FLS |
GLX | GLX351322 | A new selective NOX4 inhibitor |
GOT1 | Glutamic-oxaloacetic transaminase 1 | Catalyzes reversible transfer of α-amino group between aspartate and glutamate |
GSH | Glutathione | Plays a role in reducing ROS |
GPR30 | G-protein coupled receptor 30 | Inhibits YAP1 and suppresses ferroptosis in chondrocytes |
GPX4 | Glutathione peroxidase 4 | A pivotal enzyme in cellular defense against lipid peroxidation |
GRN | Granulin | A ferroptosis-related gene |
GSK-3β | Glycogen synthase kinase 3 beta | Inhibiting GSK-3β enhances ability to resist ferroptosis in CIA mice |
GsMTx4 | Grammostola mechanotoxin #4 | A spider venom that inhibits piezo1 |
H1299 cells | Epithelial like cell | This cell line stably expresses p53 |
HLA | Human leukocyte antigen | Different types of HLA play important in different forms of arthritis |
HO | Heme oxygenase | Antioxidant downstream protein of Nrf2, associated with ferroptosis |
HSPA5 | Heat shock protein family A member | Stabilizes GPX; identified as a ferroptosis inhibitor |
HSPB1 | Heat shock protein beta 1 | A possible regulator for ferroptosis |
ICA | Icariin | Active component found in Herba epimedii; possesses antioxidative properties and functions as an antiosteoporotic agent |
IKE | Imidazole ketone erastin | A ferroptosis inducer by inhibiting the system Xc- |
IL | Interleukin | Pro-inflammatory cytokines |
IRE | Iron-responsive element | Upregulation of TfR1, downregulation of FTH and FPN with IRPs |
IREB2 | Iron-responsive element binding protein 2 | By suppressing this protein, erastin-induced ferroptosis is restrained |
IRPs | Iron metabolic regulating proteins | Upregulation of TfR1, downregulation of FTH and FPN with IRE |
iTRAQ | Isobaric tags for relative and absolute quantification | An isobaric labeling technique employed in quantitative proteomics via tandem mass spectrometry for assessing the quantity of proteins originating from various sources within a singular experiment |
JAK/STAT | Januskinase/signal transducers and activators of transcription | Inhibiting this signaling pathway, the IL-1β and IL-6 levels in TNF-α stimulated MH7A cells are reduced |
JNK | c-JUN N terminal kinase | Inhibiting JNK-JUN-NCOA4 axis attenuated development of post-traumatic OA |
JUN | Transcription factor JUN | A hub gene involved in ferroptosis |
Keap1 | Kelch-like ECH associated protein-1 | A negative regulator of Nrf2 |
LDH | Lactate dehydrogenase | For classifying ferroptosis intensity |
LOX | Lipoxygenases | Iron-containing enzymes that do not require heme, producing lipid messengers responsible for modulating cellular inflammation by inhibiting the oxidation of PUFAs |
LPCAT3 | Lysophosphatidylcholine acyltransferae 3 | Takes part in biosynthesis and remodeling of PE, facilitating PUFA activation, influencing transmembrane characteristics of PUFAs |
LPS | Lipopolysaccharide | A large glycolipid |
m6A | N6-methyladenosine | A rare nucleoside of RNA |
MAPK | Mitogen-activated protein kinase | Plays important role in ferroptosis through nuclear factor (NF)-kB/mitogen-activated protein kinase (MAPK) signaling pathway |
MDA | Malonaldehyde | Is a derivate of PUFAs |
MEG3 | Maternally expressed 3 | A long non-coding, imprinted RNA gene expressed from maternal allele |
METTL3 | Methyltransferase-like 3 | A major methyltransferase that catalyzes formation of N6-methyladenosine (m6A) in mRNA |
MH7A | Human rheumatoid arthritis synovial cell line | Used in research |
MMA | Methyl methacrylate | A colorless liquid with an acrylic odor |
MMP | Matrix metalloproteinase | Part of the metzincin family characterized by zinc-containing multidomain structures; function as proteases |
mPEG-TK | Polyethylene glycol ketone mercaptan | Forms nanoparticles with GLX |
MTX | Methotrexate | A medication usually used for treating RA |
NCOA4 | Nuclear receptor coactivator 4 | A specific cargo receptor, facilitating autophagic ferritin breakdown |
NF-kB | Nuclear factor—kappaB | Plays important role in ferroptosis through nuclear factor (NF)-kB/mitogen-activated protein kinase (MAPK) signaling pathway |
NLRP3 | NLR family pyrin domain containing 3 | Is an inflammasome |
NOX4 | NADPH oxidase 4 | A catalytic subunit of the NADPH oxidase complex |
Nrf2 | Nuclear factor erythroid 2-related factor 2 | Controls ferroptosis-related gene expression |
OARSI | Osteoarthritis Research Society International | Score is used to classify the severity of arthritis |
P21 | Cyclin-dependent kinase inhibitor 1A | Contributes to maintaining cell balance by preventing cell death through apoptosis and acts as a ferroptosis suppressor |
P53 | Tumor protein p53 | Can induce ferroptosis via GPX4-dependent pathway or GPX4-independent pathway, tumor suppressor gene |
P65 | Nuclear factor NF-kappa-B p65 subunit | A transcription factor |
PBS | Phosphate-buffered saline | Used in research as it is a buffer solution |
PCBP | Poly-(rC)-binding protein | Act as chaperones |
PE | Phosphatidylethanolamine | Functions as key phospholipid inducing ferroptosis in cells |
PGD | Phosphogluconate dehydrogenase | A gene associated with ferroptosis |
PGE2 | Prostaglandin E2 | It is increased during ferroptosis |
Piezo1 | Piezo-type mechanosensitive ion channel component 1 | Converts diverse mechanical stimuli into electrochemical signals |
PI3K | Phosphatidylinositol3-kinase | A transferase |
Pink1 | PTEN-induced kinase 1 | Protein kinase, Pink1/Parkin-dependent mitophagy pathway has a protective effect on chondrocytes |
PLB | Plumbagin | Has anti-inflammatory, antioxidant, and anti-cancer characteristics |
PPARγ | Peroxisome proliferator activated receptor γ | Transcription factor activated by ligands; plays crucial role in controlling expression of multiple genes necessary for regulating lipid and glucose metabolism |
PTGS2 | Prostaglandin endoperoxide synthase 2 | Biomarker associated with ferroptosis |
PUFAs | Polyunsaturated fatty acids | Their characteristics play a vital role in preserving the fluidity of cell membranes, suppressing inflammatory mechanism, and reducing the release of proinflammatory cytokines by macrophages; a pivotal element for ferroptosis |
PVA | Polyvinyl acetate | An aliphatic rubbery synthetic polymer |
RA-FLS | Fibroblas-like synoviocytes in rheumatoid arthritis | Contribute to damage and inflammation within joints |
RANKL | Receptor activator of nuclear factor kB ligand | A pivotal factor for the creation of osteoclasts |
Ras | Rat sarcoma (virus) | Protein family involved in several pathways of cellular activity, often reregulated in cancer |
ROS | Reactive oxygen species | Accumulation of ROS triggers ferroptosis |
RSL3 | RAS-selective lethal 3 | A ferroptosis inducer |
SCD1 | Stearoyl-CoA desaturase | Induces ferroptosis in chondrocytes |
SCP2 | Sterol carrier protein 2 | Non-specific lipid-transfer protein found in multiple tissues and cells, plays a significant role in different diseases |
shRNA | Short hairpin RNA | Can be used to artificially silence genes using RNA interference |
SIRT1 | Sirtuin 1 | Acts as a histone deacetylase, is highly conserved, relied on nicotinamide adenine dinucleotide (NAD+), holds pivotal functions in various cellular processes |
SLC2A1 | Solute carrier family 2 member 1 | Transmembrane carrier for dehydroascorbic acid and glucose, through its activation the progression of ferroptosis is impeded |
SLC2A3 | Solute carrier family 2 member 3 | Reducing the expression of SLC2A3 triggers ferroptosis in RA-FLS |
SLC3A2 | Solute carrier family 3 member 2 | A subunit of system Xc- |
SLC3A2L | 4F2 cell-surface antigen heavy chain | LPS stimulation decreases the expression SLC3A2L |
SLC7A11 | Solute carrier family 7 member 11 | A subunit of system Xc- |
SND1 | Staphylococcal nuclease domain containing 1 | RNA-binding protein |
SP1 | Specificity protein 1 | Belongs to the SP/KLF family of transcription factors, situated within the nucleus, participates in the regulation of numerous genes within mammalian cells, can interact with various proteins |
STEAP3 | STEAP3 Metalloreductase | Converts Fe3+ to Fe2+ |
System Xc- | Cystine/glutamate transporter | Amino acid antiporter, forms a crucial part of the cellular antioxidant system |
TBHP | Tert-Butyl hydroperoxide | Can induce inflammation |
TfR 1 | Transferrin receptor 1 | Upregulation of TfR1 leads to intracellular iron accumulation |
TFRC | Transferrin receptor | A key ferroptosis-related gene |
TGF-β | Transforming growth factor-beta | Could increase susceptibility of FLSs to ferroptosis |
TGFBR1 | Transforming growth factor beta receptor 1 | Is overexpressed in the synovium of PsA patients |
TNF-α | Tumor necrosis factor alpha | Inflammatory cytokine generated by macrophages in response to acute inflammation, triggers various signaling pathways within cells |
TRPM7 | Transient receptor potential melastatin 7 | Blocking TRPM7 in chondrocytes shielded from ferroptosis |
TRPV1 | Transient receptor potential vanilloid 1 | Its activation might safeguard chondrocytes from ferroptosis |
VDAC | Voltage-dependent anion channel | Is involved in ferroptosis |
VEGF | Vascular endothelial growth factor | Plays a crucial role in regulating the formation of blood vessels during vascular development and postnatal angiogenesis, is indispensable for the development and healing of bones |
WGCNA | Weighted gene co-expression network analysis | A computational technique that evaluates the connections among measured gene transcripts, identifies groups of genes that are co-expressed in a clinically relevant manner and investigates pivotal genes within diseases pathways from the prospect of systems biology |
WNT3A | Wnt family member 3A | Is overexpressed in the synovium of PsA patients |
XO | Xanthine oxidase | Generates uric acid |
YAP1 | Yes-associated protein 1 | An augmentation of this protein inhibits ferroptosis in OA |
YY1 | Yin Yang 1 | Is a member of Gli-Kruppel zinc finger proteins, plays a role in inhibiting and activating gene promotors |
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Experiments in Animals | In Vivo | In Vitro |
---|---|---|
Inducer of ferroptosis | ||
Auranofin | mice + auranofin → died within 42 d Auranofin + Fer-1 → cell viability↑, PTGS2↓, thioredoxin reductase↓. Wild type mice + thioredoxin reductase inhibitor → lipid peroxidation↑, PTGS2↑ → Fer-1 could counteract these effects [21] | |
Erastin | Articular rat chondrocytes + erastin → cell viability↓, SLC7A11↓, FTH↓, GPX4↓, cytotoxicity↑, TRPM7↑, ACSL4↑, COX2↑ [22] | |
IL-1β | ATDC5 cells + IL-1β → lipid peroxidation↑, MDA ↑, NCOA4↑, LDH↑, FTH↓ [23] | |
IL-1β | Mice chondrocytes + IL-1β → GPX4↓, SLC7A11↓, p53↑, ACSL4↑, ROS↑ IL-1β + Fer-1 → GPX4↑, SLC7A11↑, p53↓, ACSL4↓ [24] | |
Imidazole ketone erastin (IKE) | CIA mice + IKE → RA-FLS↓, GPX4↓ [25] | |
Mechanical overload | Chondrocytes from wild type mice + intense mechanical stress by activation of piezo1 → calcium influx↑, ferroptotic damage↑, ROS↑, GSH↓ Mechanical stress + GsMTx4 → calcium influx↓, ferroptotic damage↓, ROS↓, GSH↑ [26] | |
OA-FLS exosomes | OA model group → miR-19b-3p↑, iron concentrations↑, ACSL4↑, GSH↓, GPX4↓, SLC7A11↓ OA-FLS exosomes → MDA↑, ACSL4↑, iron concentrations↑, GSH↓, GPX4↓, SLC7A11↓ [27] | Chondrocytes + IL-1β + Exo → miR-19b-3p↑, MDA↑, ACSL4↑, ROS↑, cell viability↓, GSH↓, GPX4↓, SLC7A11↓ Chondrocytes + miR(+) + Exo → cell viability↓, GPX4↓, SLC7A11↓, GSH/GSSG ratio↓, MDA↑, ROS↑, ACSL4↑, iron concentrations↑ Chondrocytes + IL-1β + miR(+) → cell viability↓, GPX4↓, SLC7A11↓, GSH↓, MDA↑, ACSL4↑, ROS↑, iron concentrations↑ Chondrocytes + IL-1β + miR(−) → cell viability↑, GPX4↑, SLC7A11↑, GSH↑, MDA↓, ACSL4↓, ROS↓, iron concentrations↓ Chondrocytes + IL-1β + miR(+) + SLC7A11 → cell viability↑, GPX4↑, SLC7A11↑, GSH↑, MDA↓, ACSL4↓, ROS↓, iron concentrations↓ [27] |
Staphylococcal nuclease domain containing 1 (SND1) | OA rats + sh-SND1 → GPX4↑, HSPA5↑, TNF-α↓, MDA↓, iron concentrations↓, cartilage tissue damage↓ [28] | Chondrocytes + sh-SND1 → HSPA5↑, GPX4↑, TNF-α↓, ROS↓, MDA↓, iron concentrations↓ Chondrocytes + sh-SND1 + sh-HSPA5 → HSPA5↓, GPX4↓, TNF-α↑, ROS, ↑ MDA↑, iron concentrations [28] |
Sterol carrier protein 2 (SCP2) | Hulth + SCP2 inhibitor → cartilage degradation↓, OARSI↓ score, iron concentrations↓, ACSL4↓, SCP2↓, MDA↓ [29] | Chondrocytes + RSL3 or SCP2 inducer or RSL3 + SCP2 inducer → SCP2↑ Chondrocytes + RSL3, RSL3 + SLCP2 → SCP2/VDAC proportion on mitochondria↑ Chondrocytes + RSL3 + SCP2 inducer → MDA↑, MMP-13↑, ROS↑, lipid hydroperoxides levels↑ Chondrocytes + RSL3 + SCP2 inhibitor → MDA↓, MMP-13↓, ROS↓, lipid hydroperoxides levels↓, cell membrane rupture↓, SCP2/VDAC proportion on mitochondria↓ [29] |
Sulfasalazine | CIA mice + sulfasalazine → GPX4↓, SLC7A11↓ [30] | |
Inhibitor of ferroptosis | ||
2′(3′)-O-(4-Benzoylbenzoyl) adenosine 5-triphosphate (BzATP) | CIA mice + erastin + BzATP → severity of arthritis↓, joint destruction↓, SLC7A11↑ [31] | |
Acetyl zingerone (AZ) | OA mice + AZ → cartilage healing↑, GPX4↑, bone deterioration↓ [32] | Rat chondrocytes + IL-1β + AZ → cell viability↑, cell proliferation↑, GPX4↑, COX2↓, MMP-13↓, MDA↓, morphological mitochondria alterations↓ [32] |
Anemoside B4 | CIA mice + anemoside B4 → GSK-3β activity↓, pain↓ via GSK-3β/Nrf2, ROS↓, NLRP3↓ [33] | |
Astragalus membranaceus (AM) | OA mice + AM → MMP-13↓, IL-1β↓, IL-6↓, TNF-α↓, GPX4↑, SLC7A11↑ [34] | |
Biochanin A (BCA) | OA mice + biochanin A → iron accumulation↓, cartilage erosion↓, Nrf2↑ [35] | Mice chondrocytes + biochanin A → cell viability↑, HO-1↑, Nrf2↑, iron accumulation↓, ROS↓ [35] |
Bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) | OA mice + BMSC-exos → OARSI↓, iron concentration↓, MDA↓, METTL3↓, ACSL4↓, GSH↑ [36] | Rat chondrocytes + IL-1β + exo → cell viability↑, GSH↑, iron concentration↓, MDA↓, ROS↓, METTL3↓, m6A↓ [36] |
Brevilin A | OA mice + brevilin A → MMP-1↓, MMP-3↓, COX2↓ [37] | Chondrocytes + IL-1β + brevilin A → PGE2↓, MMP-1↓, MMP-3↓, MDA↓, iron concentrations↓, GSH↑, GPX4↑, SIRT1↑, Nrf2↑, HO-1↑ [37] |
Calcipotriol | OA mice + calcipotriol → MMP-13↓, TGF-β1↓, GPX4↑ [38] | Chondrocytes + IL-1β + calcipotriol → ROS↓, lipid peroxidation↓, TGF-β1↓, GPX4↑ [38] |
Capsiate (CAT) | OA mice + CAT → MDA↓, H2O2↓ OA mice + HIF-1α agonist or SLC2A1 agonist → MMP-3↑, MMP-13↑, COL2↑ HIF-1α inhibitor or SLC2A1 inhibitor → MMP-3↓, MMP-13↓, COL2↓ [39] | |
Curcumin | Mice + erastin + curcumin → breakdown of cartilage↓, cartilage damage↓, MMP-9↓, MMP-13↓, aggrecan↑, collagen II↑, SLC7A11↑, GPX4↑, FTH1↑ Mice + erastin + curcumin + shNrf2 → breakdown of cartilage↑, cartilage damage↑, MMP-9↑, MMP-13↑, aggrecan↓, collagen II↓, SLC7A11↓, GPX4↓, FTH1↓ [40] | Chondrocytes + curcumin → LDH↓, MDA↓, iron concentrations↓, ROS↓, ACSL4↓, GPX4↑, SLC7A11↑, FTH1↑, Nrf2↑ Chondrocytes + erastin + curcumin + si-Nrf2 compared to erastin + curcumin → LDH↑, iron concentration↑, ACSL4↑, TFR1↑, GPX4↓, SLC7A11↓, FTH1↓, Nrf2↓ [41] |
Cyclin-dependent kinase inhibitor 1 (p21) | P21↑ in OA model of mice than in sham group [42] | Chondrocytes + IL-1β + erastin → p21↑ Knockdown p21 → proliferation rate chondrocytes↓, GSH↓, MDA↑, ROS↑, iron concentrations↑, lipid peroxidation↑ [42] |
D-mannose | OA mice + D-mannose → cartilage degradation↓, MMP-13↓, HIF-2α↓, cartilage degeneration↓, MDA↓, collagen II↑, GPX4↑ Oa mice + D-mannose + Ad-Epas1 → HIF-2α↑, MDA↑, GPX4↓ OA mice + D-mannose + Ad-Epas1 + Fer-1 → cartilage destruction↓, MDA↓, HIF-2α↓, GPX4↑ [43] | Chondrocytes + IL-1β + D-mannose → MMP-3↓, MMP-13↓, PTSG2↓, HIF-2α↓ [43] |
Ferrostatin (Fer)-1 | Chondrocytes + IL-1β + Fer-1 → cell viability↑, collagen II↑, GPX4↑, ROS↓, MDA↓, TNF-α↓, SND1↓ [28] | |
Ferrostatin (Fer)-1 | Fer-1 in mild OA → cell viability↑, GPX4↑, SLC7A11↑, MMP-13↓, ACSL4↓, p53↓ [44] | |
Forkhead box O 3 (FoxO3) | FoxO3 knocked down in mice chondrocytes → MMP-13↑, collagen II↓ Upregulation FoxO3 in IL-1β cells → ECM degradation↓, lipid peroxidation↓, ROS↓, iron concentration↓, SLC7A11↑, GPX4↑ Upregulation FoxO3 in cells treated with erastin → NF-kB↓, MAPK↓ [45] | |
G-protein coupled receptor 30 (GPR30) | Mice + DMM + G1 → OARSI↓ [46] | |
Gamma-Oryzanol (β-Ory) | Rat chondrocytes + γ-Ory → Nrf2 movement into nucleus↑, presence HO-1 in cytoplasm↑, breakdown Nrf2↓ [47] | |
Heat shock protein family A member (HSPA5) | Mice chondrocytes + Ad-HSPA5 → GPX4↑, ROS↓, TNF-α↓, MDA↓, iron concentrations↓ Chondrocytes + sh-GPX4 → GPX4↓, ROS↑, TNF-α↑, MDA↑, iron concentrations↑ [28] | |
Icariin (ICA) | Mice + icariin → iron concentrations↓, bone loss↓ [48] | Chondrocytes + icariin → iron concentrations↓ [48] |
Kukoamine A | OA mice + kukoamine A → loss of articular cartilage tissue↓, loss of cartilage matrix staining↓, MMP-1↓, MMP-3↓, COX2↓ [49] | Chondrocytes + IL-1β + kukoamine A → MDA↓, PGE2↓, MMP-1↓, MMP-3↓, iron concentration↓, translocation NF-kB p65 to nucleus↓, GSH↑, Nrf2↑, HO-1↑, SIRT1 [49] |
Liproxstatin-1 | OA mice + Liproxstatin-1 → joint swelling↓ [50] | |
Mesenchymal stem cells-derived exosomes (MSC-Exos) | OA mice + MSC-exos → TNF-α↓, INF-γ↓, IL-6↓, IL-1β↓, LDH↓, cell viability↑, GSH↑, GPX4↑, GOT1/CC2↑ [51] | Chondrocytes + exos → TNF-α↓, INF-γ↓, IL-6↓, IL-1β↓, LDH↓, iron accumulation↓, cell viability↑, GSH↑, GPX4↑, GOT1/CC2↑ [51] |
Metformin | OA mice + metformin → OARSI↓, MMP-13↓, p53↓, GPX4↑, SLC7A11↑ Erastin + metformin → OARSI↓, MMP-13↓, p53↓, GPX4↑, SLC7A11↑ [52] | |
miR-1 | OA mice + agomir-1 → OARSI↓, MMP-13↓, aggrecan↑, COL2↑, GPX4↑ [53] | |
Moderate mechanical stress | OA exercise group → joint swelling↓, cartilage damage↓, MMP-13↓, p53↓, NF-kB p65 signaling pathway↓, SLC7A11↑, GPX4↑, Nrf2↑ [54] | |
Peroxisome proliferator activated receptor γ (PPARγ) | Rat chondrocytes + RSL3 + pioglitazone (PPARγ agonist) → GPX4↑, pink1↑, parkin↑, PTGS2↓, MDA↓ [55] | |
Plumbagin (PLB) | OA mice + PLB → OARSI↓, MMP-13↓, GPX4↑ [56] | H2O2 signaling pathway can trigger MAPK signaling pathway. PLB hinders MAPK activation. [56] |
Ruscogenin | OA mice + ruscogenin → MMP-1↓, MMP-3↓, cartilage damage↓ [35] | Chondrocytes + IL-1β + ruscogenin → PGE2↓, MMP-1↓, MMP-3↓, MDA↓, iron concentration↓, GSH↑, GPX4↑, Nrf2↑, SLC7A11↑, HO-1↑ [35] |
Sarsasapogenin | Rats + DMM + sarsasapogenin → cartilage degradation↓, MMP-13↓, collagen II↑, GPX4↑, SLC7A11↑, YAP1↑ [57] | Rat chondrocytes + IL-1β + sarsasapogenin → MMP-3↓, MMP-13↓, COX2↓, aggregan↑, GPX4↑, SLC7A11↑, collagen II↑, YAP1↑ [57] |
Spermidine | Mice chondrocytes + IL1- β + spermidine → lipid peroxidation↓, MDA↓, NCOA4↓, FTH↑, GPX4↑, SLC7A11↑ [23] | |
Stearoyl-CoA desaturase (SCD1) | SCD1 knocked out in OA mice → GPX4↓, p53↑, mitochondria shrinking↑ [58] | |
Tanshinone IIA (Tan IIA) | Mouse chondrocytes + LPS + Tan IIA → ROS↓, MDA↓, iron concentration↓, GSH↑, GPX4↑ Chondrocytes + erastin + Tan IIA → cell viability↑, MMP-13↓ [34] | |
Theaflavin-3,3′ | OA mice + erastin + theaflavin-3,3′ → cartilage damage repaired and reversed compared to OA + erastin [32] | |
Transient receptor potential vanilloid 1 (TRPV1) | OA mice + TRPV1 agonist → chondrocytes↑, NCOA4↓ GPX4↓ in mice → loss of TRPV1′s anti-ferroptotic effect in OA cartilage [59] | Chondrocytes + oxidative stress reducer + TRPV1 agonist → cell viability↑, RSL3↓, ROS↓, lipid peroxidation↓, iron concentrations↓ [59] |
Experiments in Humans | FLSs | Chondrocytes |
---|---|---|
Detection of indicators for ferroptosis in arthritis | ||
ACSF2, AURKA, EGFR, KLHL24 biomarkers ferroptosis in OA | 30 samples of OA patients and 28 controls [60] | |
Increased ROS levels | RA-FLS, peripheral blood mononuclear cells from RA patients → ROS↑ in co-cultured RA-FLS and peripheral blood mononuclear cells [61] | ROS detection in mild and severe OA regions of OA patients [62] |
Iron accumulation | Iron concentrations↑, transferrin expression↓, total iron binding capacity↓ in OA patients [39] | |
Lipid peroxidation | ||
LPCAT3 and PGD as possible diagnostic markers for OA | Human tibial plateau samples from 40 OA and 10 controls [63] | |
PTGS2, ENO1 and GRN as potential ferroptosis-related biomarkers | Synovial tissue from 15 RA patients and 7 controls [64] | |
Inducer of ferroptosis: | ||
Acyl-CoA synthetase long-chain family member 4 (ACSL4) | ACSL4 silenced in chondrocytes →LDH↓, ROS↓, MDA↓, MMP-13↓, iron concentration↓, cell viability↑, GPXP4↑, GSH↑ [65] | |
CA-074Me | RA-FLS + CA-074Me → lipid oxidation rate↑, iron concentration↑, PTGS2↑, FTH1↓, SLC7A11↓, GPX4↓ [66] | |
Dexamethasone | Healthy chondrocytes stimulated with dexamethasone → ROS↑, Akt↑, FoxO3↑ [33] | |
Erastin | Chondrocytes + erastin → cell viability↓, SLC7A11↓, FTH1↓, GPX4↓, cytotoxicity↑, TRPM7↑, ACSL4↑, COX2↑ [22] | |
Galectin-1 derived peptide (G1dP3) | MH7A cells + TNF-α and G1dP3 → ROS↑, iron concentration↑ p53↑, GSH/GSSG↓, GPX4↓, SLC7A11↓ [67] | |
Glycine | RA-FLS + glycine → S-adenosyl-methionine↑, methylation of GPX4 promotor↑, GPX4↓ [68] | |
IL1-β | Chondrocytes + IL-1β → ATF3↑, TFRC↑, ROS↑, CXCL2↓, JUN↓ [69] | |
Lipopolysaccharide (LPS) | RA-FLS + LPS → ROS↑, ESCRT III↑, GPX4↓, SLC7A11↓ [70] | |
MiR-181b | Chondrocytes + erastin → miR-181b↑ MiR-181b inhibited in chondrocytes → p53↓, MMP-13↓, TFR1↓, SLC7A11↑, GPX4↑, FTH1↑, collagen II↑ [71] | |
Nuclear receptor coactivator 4 (NCOA4) | NCOA4 knocked down + LPS → PTGS2↓, iron concentration↓, cell viability↑ LPS RA-FLS under hypoxia → HIF-1α↑, FTH1↑, PTGS2↓, NCOA4↓, ROS↓, iron concentration↓ [54] | Chondrocytes + IL-1β and NCOA4 knocked down → ACSL4↓, p53↓, iron concentration↓, ROS↓, MDA↓, GPX4↑, GSH↑, cell viability↑ [72] |
OA-FLS exosomes | Exosomes derived from OA-FLS → miR-19b-3p↑ [27] | |
Piezo1 | OA chondrocytes + mechanical stress → piezo1↑, GPX4↓ [26] | |
Proinflammatory cytokines (IL-6, IL-1β, TNFα, IFN γ) | RA-FLS + TNF-α or IL-6 → absorption of transferrin-bound iron↑ RA-FLS + IL-1 or interferon γ → no significant effect [73] | |
RAS-selective lethal 3 (RSL3) | RA-FLS + RSL3 → lipid peroxidation↑, iron concentration↑, FTH1↓, SLC7A11↓, SLC2A3↓, GPX4↓ [74] | |
Specificity protein 1 (Sp1) | Chondrocytes + IL-1β → Sp1 Sp1 silenced in chondrocytes → Sp1↓, ACSL4↓ Sp1 overexpressed in chondrocytes → ACSL4↑ [65] | |
Sterol carrier protein 2 (SCP2) | Chondrocytes of OA patients → SCP2↑, MDA↑, iron concentration↑, lipid peroxidation↑, GPX4↓ Chondrocytes + SCP2 inhibitor → cell viability↑ [29] | |
Sulfasalazine | RA-FLS + sulfasalazine → p-PI3K/PI3K↓, p-AKT/AKT↓, p-ERK1/2/ERK1/2↓, p53↑ [30] | |
Wasp venom (WV) I and WVII | MH7A cells + TNF-α and WVI or WVII → IL-1β↓, IL-6↓, JAK/STAT signaling pathway↓, ROS↑, GPX4↓ [75] | |
Yin Yang 1 (YY1) | RA-FLS + LPS + SIRT1 + YY1 → ROS↑, iron concentration↑ [76] | |
Inhibitor of ferroptosis: | ||
Baicalin | Chondrocytes + IL-1β + baicalin → cell viability↑, GPX4↑, SLC7A11↑, Nrf2↑, iron concentration↓, p53↓, ACSL4↓, ROS↓, MDA↓ [77] | |
Endosomal sorting complex required for transport (ESCRT)-III | Subunit of ESCRT-III knocked down → ROS↑, GPX4↓, SLC7A11↓ [70] | |
Enolase 1 (ENO1) | ENO1 knocked down in RA-FLS → ROS↑, iron concentration↑, cell mortality↑, ACO1↑ [64] | |
Epigallocatechin-3-gallate-based nanodrugs (ES NDs) | Chondrocytes + H2O2 + ES NDs → ROS↓, iron concentration↓, MDA↓, ACSL4↓, GPX4↑, FTH1↑ [62] | |
Ferrostatin (Fer)-1 | Chondrocytes + IL-1β + Fer-1 → cell viability↑, cell proliferation↑, GPX4↑, SLC7A11↑, ROS↓, MDA↓, iron concentration↓, ACSL4↓, p53↓ [24] | |
G-protein coupled receptor 30 (GPR30) | Chondrocytes + erastin + G1 → cell viability↑, FTH1↑, GPX4↑, YAP1↑, ROS↓, lipid peroxidation↓ YAP1 knocked down → protective effects of G1↓ [46] | |
Icariin (ICA) | RA-FLS + LPS + ICA → cell death↓, iron concentration↓, GPX4↑, RA-FLS + RSL3 + ICA → Xc-/GPX4↑ [78] | |
Long noncoding RNA (lncRNA) maternally expressed 3 (MEG3) | Chondrocytes + erastin + siMEG3 → SLC7A11↓, GPX4↓, cell viability↓, MDA↑, miR-885-5p↑ lncRNA MEG3 upregulated in chondrocytes → miR-885-5p↓, SLC7A11↑, GPX4↑ Chondrocytes + erastin + MEG3 → MDA↓, cell viability↑ OA samples → lncRNA MEG3↓, SLC7A11↓, miR-885-5p↑ [79] | |
miR-1 | OA cartilage samples → miR-1↓, CX43↑ OA chondrocytes + miR-1 → cell proliferation↑, aggrecan↑, COL2↑, MMP-13↓, CX43↓ Chondrocytes + CX43 → aggrecan↓, COL2↓, MMP-13↑ [53] | |
Moderate mechanical stress | Chondrocytes + IL-1β + CTS → MMP-3↓, MMP-13↓, p53↓, NF-kB p65 signaling pathway↓, SLC7A11↑, GPX4↑, Nrf2↑ [80] | |
Puerarin | Chondrocytes + IL-1β + puerarin → cell viability↑, IL-1β↓, IL-6↓, TNF-α↓ [81] | |
Semaphorin 5A | RA-FLS + semaphorin 5A → PI3K/AKT/mTOR signaling pathway↑, GPX4↑ [82] | |
Sirtuin 1 (SIRT1) | RA-FLS + LPS and SIRT1 was overexpressed → cell viability↑, ROS↓, iron concentration↓ [76] | |
Theaflavin-3,3′ | Chondrocytes + erastin + theaflavin-3,3 → ROS↓, iron concentration↓, FTH1↑, GPX4↑, SLC7A11↑, Nrf2↑, Keap1↑ [32] |
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Bieri, S.; Möller, B.; Amsler, J. Ferroptosis in Arthritis: Driver of the Disease or Therapeutic Option? Int. J. Mol. Sci. 2024, 25, 8212. https://doi.org/10.3390/ijms25158212
Bieri S, Möller B, Amsler J. Ferroptosis in Arthritis: Driver of the Disease or Therapeutic Option? International Journal of Molecular Sciences. 2024; 25(15):8212. https://doi.org/10.3390/ijms25158212
Chicago/Turabian StyleBieri, Shania, Burkhard Möller, and Jennifer Amsler. 2024. "Ferroptosis in Arthritis: Driver of the Disease or Therapeutic Option?" International Journal of Molecular Sciences 25, no. 15: 8212. https://doi.org/10.3390/ijms25158212