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  2. Mettl3 inhibits the apoptosis and autophagy of chondrocytes in inflammation through mediating Bcl2 stability via Ythdf1-mediated m6A modification

Mettl3 inhibits the apoptosis and autophagy of chondrocytes in inflammation through mediating Bcl2 stability via Ythdf1-mediated m6A modification

  • Bone. 2022 Jan;154:116182. doi: 10.1016/j.bone.2021.116182.
Ying He 1 Wei Wang 2 Xiaoxiao Xu 1 Beining Yang 1 Xijie Yu 1 Yanru Wu 1 Jiawei Wang 3
Affiliations

Affiliations

  • 1 The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China.
  • 2 Departments of Pancreatic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China.
  • 3 The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China. Electronic address: wb000238@whu.edu.cn.
Abstract

N6-methyladenosine (m6A) methylation is one of the most common internal modifications in eukaryotic messenger RNA occurring on N6 nitrogen of adenosine. However, the roles of m6A in temporomandibular joint osteoarthritis (TMJ OA) are still elusive. Here, we investigate the function and mechanism of methyltransferase-like 3 (METTL3) in chondrocytes in inflammation. We found that the expression of METTL3 decreased both in vivo TMJ OA mice and in vitro inflammatory stimulation. Functionally, loss and gain studies illustrated that METTL3 inhibited the Apoptosis and Autophagy of chondrocytes induced by TNF-α stimulation in vitro. METTL3 Inhibitor, S-adenosylhomocysteine (SAH) promoted the Apoptosis and Autophagy of chondrocytes with inflammation in vitro and aggravated the degeneration of chondrocytes and subchondral bone in monosodium iodoacetate (MIA) induced TMJ OA mice in vivo. Mechanistically, the bioinformatics analysis, m6A-RNA immunoprecipitation (MeRIP) and RNA immunoprecipitation (RIP) were used to identify that Bcl2 mRNA was the downstream target of METTL3 for m6A modification. Furthermore, the results revealed that Yth m6A RNA binding protein 1 (Ythdf1) mediated the stability of Bcl2 mRNA catalyzed by METTL3. Co-immunoprecipitation (Co-IP) showed that Bcl2 protein interacted with Beclin1 protein in chondrocytes induced by TNF-α stimulation. In conclusion, our findings identify that METTL3 inhibits the Apoptosis and Autophagy of chondrocytes in inflammation through m6A/Ythdf1/Bcl2 signal axis which provides promising therapeutic strategy for TMJ OA.

Keywords

Apoptosis; Autophagy; B-cell lymphoma 2; Chondrocyte; Inflammation; Methyltransferase-like 3; N(6)-methyladenosine.

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