RNA Modifications in Osteoarthritis: Epitranscriptomic Insights into Pathogenesis and Therapeutic Targets
Abstract
1. Introduction
2. Epitranscriptomic Modifications
3. Epitranscriptomic Modifications in OA
4. N6-Methyladenosine (m6A)
4.1. Impact of m6A Modification on OA-Related mRNAs
4.1.1. Inflammation
4.1.2. ECM Degradation
4.1.3. Ferroptosis
4.1.4. Pyroptosis
4.1.5. Cellular Senescence
4.1.6. Autophagy
Pathogenic Mechanism | Target of Modification | Models | Effect on OA Pathogenesis | References |
---|---|---|---|---|
Inflammation | mRNA (IL-6, IL-8, IL-12, and TNF-α) | In vitro: IL-1β-treated mouse chondrocyte cell line ATDC5 In vivo: Collagenase-induced OA mouse model | METTL3 regulates OA progression by modulating pro-inflammatory factors, such as IL-6, IL-8, IL-12, and TNF-α, and NF-κB signaling | [76] |
mRNA (NLRP3) | In vivo: DMM-induced OA mouse model In vitro: IL-1β-treated human OA primary chondrocytes | Targeting METTL3 via miR-1208 decreases NLRP3 mRNA levels and activity, thereby reducing inflammatory factor levels | [78] | |
ECM Degradation | mRNA (MMP-1, MMP-3, MMP-13, TIMP-1, TIMP-2) | In vitro: IL-1β-treated human chondrocyte Human OA cartilage explants | METTL3 overexpression modulates ECM degradation by modulating the TIMP/MMP balance | [61] |
mRNA (MMP-13, and COL2A1) | In vitro: IL-1β-treated mouse chondrocyte cell line ATDC5 In vivo: Collagenase-induced OA mouse model | METTL3 deletion reduces MMP-13 expression and enhances that of COL2A1 | [76] | |
mRNA (SOX9, COL2A1) | Human OA cartilage explants | METTL3 regulates SOX9 expression and suppresses COL2A1 levels | [77] | |
mRNA (COL2A1, ADAMTS5 and MMP-13) | In vivo: DMM-induced OA mouse model Human OA cartilage explants | METTL3 inhibition increases COL2A1 and aggrecan levels while decreasing ADAMTS5 and MMP-13 expression | [78] | |
mRNA (STAT1) | In vitro: IL-1β-treated rat primary chondrocytes In vivo: ALCT induced OA rat model Human OA cartilage explants | METTL3 enhances the expression of STAT1, and upregulates ADAMTS12 | [79] | |
mRNA (RPL38 and SOCS2) | In vitro: IL-1β-treated human OA primary chondrocytes In vivo: DMM-induced OA mouse model Human OA cartilage explants | Silencing RPL38 upregulates SOCS2 expression via METTL3-mediated methylation | [80] | |
mRNA ((Ctsk) | In vitro: IL-1β-treated rat primary chondrocytes In vivo: T-2 toxin-induced cartilage injury rat model | T-2 toxin induces cartilage damage via METTL3-m6A methylation of Ctsk | [82] | |
mRNA (CA12) | In vitro: IL-1β-treated human chondrocyte Human normal and OA cartilage explants | WTAP enhances CA12 mRNA stability and leads to chondrocyte apoptosis | [83] | |
mRNA (FRZB) | In vivo: DMM-induced OA mouse model Human OA cartilage explants | WTAP-mediated m6A modification reduces FRZB expression, and activates the Wnt/β-catenin pathway | [68] | |
mRNA (Runx2) | In vitro: LPS-treated mouse primary NP cells In vivo: LPS-induced IVDD mouse model, MIA-induced OA rat model | ALKBH5 facilitates Runx2 mRNA demethylation and upregulates MMPs and ADAMTSs | [86,87] | |
mRNA (SMAD2) | In vitro: IL-1β-treated mouse primary chondrocytes In vivo: DMM-induced OA mouse model Human OA cartilage explants | Decreased levels of FTO stabilizes SMAD2 mRNA and regulates TGF-β signaling | [88] | |
Ferroptosis | mRNA (GPX4) | In vitro: IL-1β-treated mouse primary chondrocytes In vivo: MIA-induced OA rat model | Silencing METTL14 suppresses GPX4 mRNA m6A modification and inhibits ferroptosis | [62] |
mRNA (HMGB1) | In vitro: IL-1β-treated rat primary chondrocytes In vivo: MIA-induced OA rat model | METTL3 promotes m6A methylation of HMGB1 mRNA, and increases ferroptosis | [90] | |
mRNA (SLC7A11) | In vivo: Acupuncture-induced IVDD rat model | YTHDF1 and HIF-1α overexpression reduces NPC ferroptosis by promoting SLC7A11 translation | [91] | |
Pyroptosis | mRNA (NeK7) | In vitro LPS-treated human OA primary chondrocytes In vivo: DMM-induced OA mouse model Human OA cartilage explants | METTL3 knockdown reduces NEK7 mRNA levels, and suppresses chondrocyte pyroptosis | [93] |
Cell senescence | mRNA (SLC1A5) | In vitro: H2O2-treated primary rat osteoblasts In vivo: si-Igf2bp2 and Cpd-564-treated osteoporosis rat model | METTL3 and IGF2BP2 inhibition modulates the METTL3/IGF2BP2-SLC1A5 axis and reduces osteoblast senescence | [97] |
mRNA (CYP1B1) | In vitro: Human normal cartilage explants In vivo: ALCT induced OA mice model | m6A methylation stabilizes CYP1B1 mRNA and promotes MSC senescence | [95] | |
Autophagy | mRNA (ATG7) | In vivo: DMM-induced OA mouse model Human normal cartilage explants | METTL3-mediated m6A modification reduces ATG7 mRNA and impairs autophagy | [100] |
mRNA (PIK3R5) | In vitro: IL-1β-treated rat primary chondrocytes In vivo: MIA-induced OA rat model Human OA cartilage explants | FTO activates the PI3K/AKT/mTOR axis | [101] |
4.2. Impact of m6A Modification on Non-Coding RNAs
4.2.1. MicroRNAs (miRNAs)
4.2.2. Long Non-Coding RNAs (lncRNAs)
4.2.3. Circular RNAs (circRNAs)
Type of Non-Coding RNAs | Target of Modification | Models | Effect on OA Pathogenesis | References |
---|---|---|---|---|
Micro RNAs (miRNAs) | miR-126-5p | In vitro: IL-1β-treated human OA primary chondrocytes Human OA cartilage explants | METTL3 regulates miR-126-5p maturation and inhibits the PI3K/Akt axis | [102] |
miR-92b-5p | Human OA cartilage explants | WTAP enhances miR-92b-5p maturation, thereby reducing TIMP4 expression | [103] | |
pri-miR-515-5p | In vitro: LPS-treated human chondrocyte In vivo: MIA-induced OA rat model | FTO modulates pri-miR-515-5p activity and regulates the TLR4/MyD88/NF-κB pathway | [104] | |
pri-miR-3591 | Human OA cartilage explants | FTO regulates pri-miR-3591 maturation, and suppresses its inhibitory effects on PRKAA2 | [105] | |
Long non-coding RNAs (lncRNAs) | lncRNA: LINC00680 | In vitro: IL-1β-treated human chondrocytes | METTL3 upregulates LINC00680, which interacts with SIRT1 mRNA | [106] |
lncRNA: IGFBP7-OT | In vitro: LPS-treated human chondrocytes In vivo: Mouse model of MIA-induced OA Human OA cartilage explants | METTL3-mediated m6A modification of IGFBP7-OT regulates the DNMT1/DNMT3a-IGFBP7 axis | [107] | |
lncRNA: FAS-AS1 | In vitro: IL-1β-treated human chondrocytes In vivo: ALCT induced OA rat model | METTL14 upregulates FAS-AS1, and activates the JAK/STAT3 signaling pathway | [108] | |
lncRNA: NORAD | Human normal and DDD NP tissues | WTAP-mediated m6A modification of NORAD regulates the PUMILIO/E2F3 pathway, promoting senescence | [109] | |
lncRNA: AC008 | In vitro: IL-1β-treated human normal primary chondrocytes In vivo: MIA-induced OA rat model Human normal and OA cartilage explants | FTO suppresses AC008 transcription, thereby elevating miR-328-3p levels and downregulating AQP1 and ANKH | [110] | |
lncRNA: HS3ST3B1-IT1 | In vivo: MIA-induced OA mouse model Human normal and OA cartilage explants | ALKBH5-mediated demethylation stabilizes HS3ST3B1-IT1 RNA | [111] | |
lncRNA: AK311120 | In vitro: Human adipose-derived stem cells (hASCs) In vivo: Mouse model of mandibular defect | ALKBH5 demethylates lnc-AK311120, regulates MAP2K7/JNK signaling, and promotes osteogenesis | [112] | |
lncRNA: LOC102555094 | In vivo: Acupuncture-induced IVDD rat model | Demethylation of LOC102555094 by ZFP217 and FTO activates the miR-431/GSK-3β/Wnt pathway, which promotes IVDD | [113] | |
Circular RNAs (circRNAs) | circRNA: circMYO1C | Human normal and OA cartilage explants | An m6A-modified circMYO1C enhances HMGB1 mRNA stability, promoting chondrocyte apoptosis | [115] |
circular RNA: circRERE | In vitro: IL-1β-treated human chondrocytes In vivo: DMM-induced OA mouse model | m6A modification promotes circRERE degradation and contributes to OA pathogenesis | [116] |
5. 5-Methylcytosine (m5C)
6. N7-Methylguanosine (m7G)
7. Pseudouridylation (Ψ)
8. 2′-O-Ribose Methylation (2′-O-Me)
9. Polyadenylation
10. Therapeutic Potential of Targeting RNA Modifications in OA
11. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
2′-O-Me | 2′-O-ribose methylation |
ADAMTS | A Disintegrin and Metalloproteinase with Thrombospondin Motifs |
ALKBH5 | AlkB Homolog 5 |
ECM | Extracellular Matrix |
EGFR | Epidermal Growth Factor Receptor |
EIF4E | Eukaryotic Translation Initiation Factor 4E |
EIF4E2 | Eukaryotic Translation Initiation Factor 4E2 |
hm5C | Cytosine-5-Hydroxymethylation |
IGF2BP1 | Insulin-like Growth Factor 2 Binding Protein 1 |
IL-12 | Interleukin 12 |
IL1 α | Interleukin 1 Alpha |
IL1β | Interleukin 1 Beta |
IL-6 | Interleukin 6 |
IL-8 | Interleukin 8 |
IVDD | Intervertebral Disc Degeneration |
KOA | Knee Osteoarthritis |
lncRNA | Long Non-Coding RNA |
m1A | Methylation of Adenosine at Position N1 |
m5C | 5-methylcytosine |
m6A | N6-methyladenosine |
m7G | N7-methylguanosine |
MeRIP-Seq | Methylated RNA Immunoprecipitation Sequencing |
METTL | Methyltransferase-Like |
miCLIP | Methylation-induced Crosslinking and Immunoprecipitation |
miRNA | MicroRNA |
mRNA | Messenger RNA |
ROS | Reactive Oxygen Species |
rRNA | Ribosomal RNA |
SONFH | Steroid-Associated Osteonecrosis of the Femoral Head |
SUMOylation | Small Ubiquitin-like Modifier Modification |
TET | Ten-Eleven Translocation |
TGFβ1 | Transforming Growth Factor Beta 1 |
tRNA | Transfer RNA |
VDR | Vitamin D Receptor |
Ψ | Pseudouridylation |
OA | Osteoarthritis |
PI3K/AKT/mTOR | Phosphoinositide 3-Kinase/Protein Kinase B/Mechanistic Target of Rapamycin |
WTAP | Wilms Tumor 1-Associated Protein |
YTH | YTH Domain-Containing Proteins |
ZFP217 | Zinc Finger Protein 217 |
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Type of Modifications | Target of Modification | Models | Effect on OA Pathogenesis | References |
---|---|---|---|---|
m5C Methylation | mRNA (Sox9) | In vivo: Surgically induced full-thickness osteochondral defect model in rat | NSUN4 methylates the 3′ UTR of Sox9 mRNA, regulating chondrogenic differentiation | [125] |
m7G Methylation | Mitochondrial transfer RNA (mt-tRF3b-LeuTAA) | In vitro: IL-1β-treated human OA primary chondrocytes In vivo: DMM-induced OA mouse model | METTL1-mediated m7G modification promotes mt-tRF3b-LeuTAA, SIRT3 SUMOylation, and cartilage degeneration | [127] |
Pseudouridylation | rRNA (at sites 28S- 4966) | In vitro: IL-1β-treated human normal primary chondrocytes | OA microenvironment alters site-specific changes in rRNA pseudouridylation | [133] |
2′-O-ribose methylation (2′-O-Me) | rRNA (U14in 5.8S) | In vitro: IL-1β-stimulated human chondrocytes | Reduced 2′-O-Me of U14 in 5.8S rRNA impairs ribosome function and contributes to OA pathogenesis | [135] |
Polyadenylation | mRNA (OSMR) | Human OA cartilage explants | Disruption of polyadenylation alters 3′UTR length, stabilizes OSMR mRNA, and promotes ECM degradation | [138] |
mRNA (Runx2, MMPS-3/-13, ADAMTS-4) | In vivo: DMM-induced OA mouse model Human OA cartilage explants | Cordycepin inhibits polyadenylation, and reduces Runx2 and MMP-3/-13 levels | [139] |
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Radbakhsh, S.; Najar, M.; Merimi, M.; Benderdour, M.; Fernandes, J.C.; Martel-Pelletier, J.; Pelletier, J.-P.; Fahmi, H. RNA Modifications in Osteoarthritis: Epitranscriptomic Insights into Pathogenesis and Therapeutic Targets. Int. J. Mol. Sci. 2025, 26, 4955. https://doi.org/10.3390/ijms26104955
Radbakhsh S, Najar M, Merimi M, Benderdour M, Fernandes JC, Martel-Pelletier J, Pelletier J-P, Fahmi H. RNA Modifications in Osteoarthritis: Epitranscriptomic Insights into Pathogenesis and Therapeutic Targets. International Journal of Molecular Sciences. 2025; 26(10):4955. https://doi.org/10.3390/ijms26104955
Chicago/Turabian StyleRadbakhsh, Shabnam, Mehdi Najar, Makram Merimi, Mohamed Benderdour, Julio C. Fernandes, Johanne Martel-Pelletier, Jean-Pierre Pelletier, and Hassan Fahmi. 2025. "RNA Modifications in Osteoarthritis: Epitranscriptomic Insights into Pathogenesis and Therapeutic Targets" International Journal of Molecular Sciences 26, no. 10: 4955. https://doi.org/10.3390/ijms26104955
APA StyleRadbakhsh, S., Najar, M., Merimi, M., Benderdour, M., Fernandes, J. C., Martel-Pelletier, J., Pelletier, J.-P., & Fahmi, H. (2025). RNA Modifications in Osteoarthritis: Epitranscriptomic Insights into Pathogenesis and Therapeutic Targets. International Journal of Molecular Sciences, 26(10), 4955. https://doi.org/10.3390/ijms26104955