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 7

NAC supplementation partially rescues the impaired osteogenesis in Mettl5-KO mice.

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NAC supplementation partially rescues the impaired osteogenesis in Mettl...
(A) Representative images of ALP and ARS staining in MSCs from WT and Mettl5-KO mice after osteogenic induction with vehicle or NAC treatment. n = 3. (B and C) Quantitative analyses of ALP activity and ARS staining in MSCs from WT and Mettl5-KO mice after osteogenic induction with vehicle or NAC treatment. n = 3. (D) Representative images of whole-mount skeletal staining in neonatal WT and Mettl5-KO mice after vehicle or NAC treatment. Scale bar: 4 mm. n = 3. (E) Representative Von Kossa staining and quantification of femur length and mineralized area of femurs from P1 WT and Mettl5-KO mice after vehicle or NAC treatment. Scale bar: 400 μm. n = 5. (F) Representative Von Kossa staining and quantification of mineralized area of femurs from P1 WT and Prrx1Cre Mettl5fl/fl mice after vehicle or NAC treatment. Scale bar: 400 μm. n = 3. (G) MicroCT reconstructions of trabecular bone (top) and cortical bone (bottom) in femurs from 6-week-old male WT and Mettl5-KO mice after vehicle or NAC treatment, with corresponding quantitative analyses of trabecular and cortical bone parameters. Scale bar: 400 μm. n = 6. (H) Representative Von Kossa staining of femurs from 6-week-old male WT and Mettl5-KO mice after vehicle or NAC treatment. Scale bar: 400 μm. n = 3. (I) Representative Calcein double-labeling images of femoral trabecular bone from 6-week-old male WT and Mettl5-KO mice and corresponding quantification of mineral apposition rate (MAR). Scale bar: 50 μm. n = 5. Data are expressed as mean ± SD; P values were determined by 2-way ANOVA.