METTL5 deficiency impairs osteogenesis through OSER1-dependent antioxidant regulation
Kexin Lei, Qi Yin, Qiwen Li, Qian Wang, Zhong Zhang, Fei Xue, Ruoshi Xu, Xinyi Zhou, Lin Peng, Shoichiro Kokabu, Shuibin Lin, Quan Yuan
Kexin Lei, Qi Yin, Qiwen Li, Qian Wang, Zhong Zhang, Fei Xue, Ruoshi Xu, Xinyi Zhou, Lin Peng, Shoichiro Kokabu, Shuibin Lin, Quan Yuan
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Research Article Bone biology Cell biology

METTL5 deficiency impairs osteogenesis through OSER1-dependent antioxidant regulation

Abstract

Methyltransferase-like 5 (METTL5) is a methyltransferase responsible for rRNA N6-methyladenosine (m6A) modification, mutations in which are associated with skeletal abnormalities and cognitive deficits. Despite METTL5’s clinical relevance, the molecular mechanisms underlying METTL5-related genetic disorders remain poorly understood. In this study, we demonstrated that Mettl5 KO led to reduced bone mass and smaller body size in mice and impaired the osteogenic differentiation of mesenchymal stem cells. Mechanistically, Mettl5 deficiency decreased the translation efficiency of oxidative stress–responsive serine-rich protein 1 mRNA, downregulated the expression of key antioxidant genes, and diminished antioxidant capacity. Importantly, administration of the antioxidant N-acetylcysteine (NAC) partially rescued skeletal defects in Mettl5-KO mice. These findings reveal a critical role for METTL5 in antioxidant defense and suggest that NAC supplementation may represent a promising therapeutic strategy for METTL5-related disorders.

Authors

Kexin Lei, Qi Yin, Qiwen Li, Qian Wang, Zhong Zhang, Fei Xue, Ruoshi Xu, Xinyi Zhou, Lin Peng, Shoichiro Kokabu, Shuibin Lin, Quan Yuan

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Figure 6

OSER1 supports antioxidant defense in osteogenic lineage cells.

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OSER1 supports antioxidant defense in osteogenic lineage cells. (A) Repr...
(A) Representative fluorescent probe staining and corresponding quantification of glutathione signal in si-Control and si-Oser1 MC3T3-E1 cells. Scale bar: 40 μm. n = 5. (B and C) Representative images of Calcein-AM and PI staining in si-Control and si-Oser1 MC3T3-E1 cells treated with increasing concentrations of H2O2, with corresponding quantification of the live cell ratios at each concentration. Scale bar: 100 μm. n = 3. (D) qRT-PCR analysis of antioxidant-related gene expression in si-Control and si-Oser1 MC3T3-E1 cells treated with vehicle or 200 μM H2O2. n = 3. (E) Representative Western blot images and corresponding quantification showing antioxidant-related protein levels in si-Control and si-Oser1 MC3T3-E1 cells treated with vehicle or 200 μM H2O2. n = 3. (F) Representative images and quantification showing the effects of N-acetylcysteine (NAC) treatment in si-Control and si-Oser1 MC3T3-E1 cells after exposure to 200 μM H2O2, with or without NAC. Scale bar: 100 μm. n = 3. (G) qRT-PCR analysis of Sod1 and Cat in WT and Mettl5-KO MSCs with vehicle treatment or adenovirus-mediated Oser1 overexpression. n = 3. Data are expressed as mean ± SD; P values were determined by 2-tailed Student’s t test (A and C) and 2-way ANOVA (D–G).