Connective tissue research · 2026
Mettl3-modified lncRNA Snhg16 aggravates osteoarthritis via promoting chondrocyte ferroptosis by regulating Snd1/Gpx4 axis.
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Li Qiang, Ye Xiangyang, Yuan Xiao, Chen Shengtao, Tang Haibin, Shen Liming, He Shangwen
Аннотация
PURPOSE/AIM: Long noncoding RNA (lncRNA) small nucleolar RNA host gene 16 (Snhg16) has been confirmed to accelerate osteoarthritis (OA) progress. However, its regulatory mechanism has not been fully elucidated.
MATERIALS AND METHODS: Interleukin-1β (IL-1β)-induced ATDC5 chondrocytes were used to mimic OA cell models, and destabilization of medial meniscus (DMM) surgery was performed to construct OA mice models. The expression levels of Snhg16, glutathione peroxidase 4 (Gpx4), staphylococcal nuclease domain-containing 1 (Snd1), methyltransferase-like 3 (Mettl3) and extracellular matrix (ECM) degradation-related markers were detected by qRT-PCR or western blot. Besides, glutathione (GSH), malondialdehyde (MDA), Fe2+ and lipid reactive oxygen species (ROS) levels were detected to evaluate cell ferroptosis. The interaction between Snd1 and Snhg16 or Gpx4 was evaluated by RNA pull-down and RNA immunoprecipitation (RIP) assays. The stability of Gpx4 mRNA and Snhg16 was examined using actinomycin D assay. Methylated RNA immunoprecipitation (MeRIP) assay was used to measure the regulation of Mettl3 on Snhg16.
RESULTS: Snhg16 downregulation repressed IL-1β-induced chondrocyte ferroptosis and ECM degradation. Also, silencing of Snhg16 alleviated cartilage tissue damage in OA mice models. In the terms of mechanism, Snhg16 inhibited the stability of Gpx4 mRNA via interacting with Snd1. Moreover, Mettl3 enhanced Snhg16 stability by m6A modification. Functional experiments showed that Mettl3 knockdown suppressed IL-1β-induced ferroptosis and ECM degradation through regulating the Snhg16/Snd1/Gpx4 axis.
CONCLUSIONS: Mettl3-mediated m6A modification of Snhg16 facilitated ferroptosis and ECM degradation to aggravate OA process via regulating Snd1/Gpx4 axis, providing a novel target for OA treatment.
MATERIALS AND METHODS: Interleukin-1β (IL-1β)-induced ATDC5 chondrocytes were used to mimic OA cell models, and destabilization of medial meniscus (DMM) surgery was performed to construct OA mice models. The expression levels of Snhg16, glutathione peroxidase 4 (Gpx4), staphylococcal nuclease domain-containing 1 (Snd1), methyltransferase-like 3 (Mettl3) and extracellular matrix (ECM) degradation-related markers were detected by qRT-PCR or western blot. Besides, glutathione (GSH), malondialdehyde (MDA), Fe2+ and lipid reactive oxygen species (ROS) levels were detected to evaluate cell ferroptosis. The interaction between Snd1 and Snhg16 or Gpx4 was evaluated by RNA pull-down and RNA immunoprecipitation (RIP) assays. The stability of Gpx4 mRNA and Snhg16 was examined using actinomycin D assay. Methylated RNA immunoprecipitation (MeRIP) assay was used to measure the regulation of Mettl3 on Snhg16.
RESULTS: Snhg16 downregulation repressed IL-1β-induced chondrocyte ferroptosis and ECM degradation. Also, silencing of Snhg16 alleviated cartilage tissue damage in OA mice models. In the terms of mechanism, Snhg16 inhibited the stability of Gpx4 mRNA via interacting with Snd1. Moreover, Mettl3 enhanced Snhg16 stability by m6A modification. Functional experiments showed that Mettl3 knockdown suppressed IL-1β-induced ferroptosis and ECM degradation through regulating the Snhg16/Snd1/Gpx4 axis.
CONCLUSIONS: Mettl3-mediated m6A modification of Snhg16 facilitated ferroptosis and ECM degradation to aggravate OA process via regulating Snd1/Gpx4 axis, providing a novel target for OA treatment.