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 3

METTL5 regulates the translation of OSER1.

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METTL5 regulates the translation of OSER1. (A) Methylated RNA IP–qPCR an...
(A) Methylated RNA IP–qPCR analysis of 18S rRNA m6A enrichment in MSCs derived from WT and Prrx1Cre Mettl5fl/fl mice. n = 3. (B) Methylated RNA IP–qPCR analysis of 18S rRNA m6A enrichment in MC3T3-E1 cells transfected with si-Control and si-Mettl5. n = 3. (C) Volcano plot of differentially translated genes identified by ribosome profiling in MSCs. Oser1 and Mettl5 are highlighted among genes with significant altered translation efficiency. Threshold: |log2(FC)| > 1, P < 0.05. (D) Relative Firefly/Renilla luciferase activity in MC3T3-E1 cells transfected with an Oser1 dual-luciferase reporter plasmid in the si-Control and si-Mettl5 groups. n = 6. (E) qRT-PCR analysis of Oser1 mRNA levels in MSCs from WT and Mettl5-KO mice. n = 3. (F) Representative Western blot images and quantification of OSER1 protein levels in WT and Mettl5-KO MSCs. n = 3. (G) Representative immunofluorescence images showing OSER1 expression in WT and Mettl5-KO MSCs, with corresponding quantification. Scale bar: 10 μm. n = 3. Data are expressed as mean ± SD; P values were determined by 2-tailed Student’s t test.