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Metabolic rewiring during bone development underlies tRNA m7G–associated primordial dwarfism
Qiwen Li, … , Demeng Chen, Quan Yuan
Qiwen Li, … , Demeng Chen, Quan Yuan
Published September 10, 2024
Citation Information: J Clin Invest. 2024;134(20):e177220. https://doi.org/10.1172/JCI177220.
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Research Article Bone biology Metabolism Article has an altmetric score of 1

Metabolic rewiring during bone development underlies tRNA m7G–associated primordial dwarfism

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Abstract

Translation of mRNA to protein is tightly regulated by transfer RNAs (tRNAs), which are subject to various chemical modifications that maintain structure, stability, and function. Deficiency of tRNA N7-methylguanosine (m7G) modification in patients causes a type of primordial dwarfism, but the underlying mechanism remains unknown. Here we report that the loss of m7G rewires cellular metabolism, leading to the pathogenesis of primordial dwarfism. Conditional deletion of the catalytic enzyme Mettl1 or missense mutation of the scaffold protein Wdr4 severely impaired endochondral bone formation and bone mass accrual. Mechanistically, Mettl1 knockout decreased abundance of m7G-modified tRNAs and inhibited translation of mRNAs relating to cytoskeleton and Rho GTPase signaling. Meanwhile, Mettl1 knockout enhanced cellular energy metabolism despite incompetent proliferation and osteogenic commitment. Further exploration revealed that impairment of Rho GTPase signaling upregulated the level of branched-chain amino acid transaminase 1 (BCAT1) that rewired cell metabolism and restricted intracellular α-ketoglutarate (αKG). Supplementation of αKG ameliorated the skeletal defect of Mettl1-deficient mice. In addition to the selective translation of metabolism-related mRNAs, we further revealed that Mettl1 knockout globally regulated translation via integrated stress response (ISR) and mammalian target of rapamycin complex 1 (mTORC1) signaling. Restoring translation by targeting either ISR or mTORC1 aggravated bone defects of Mettl1-deficient mice. Overall, our study unveils a critical role of m7G tRNA modification in bone development by regulation of cellular metabolism and indicates suspension of translation initiation as a quality control mechanism in response to tRNA dysregulation.

Authors

Qiwen Li, Shuang Jiang, Kexin Lei, Hui Han, Yaqian Chen, Weimin Lin, Qiuchan Xiong, Xingying Qi, Xinyan Gan, Rui Sheng, Yuan Wang, Yarong Zhang, Jieyi Ma, Tao Li, Shuibin Lin, Chenchen Zhou, Demeng Chen, Quan Yuan

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Figure 2

Wdr4-R215L mutation leads to bone growth defects.

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Wdr4-R215L mutation leads to bone growth defects.
(A and B) Western blo...
(A and B) Western blot analysis of METTL1 and WDR4 expression in WT and Wdr4R215L/R215L mouse limb tissue lysates at E16.5. n = 7. (C and D) Representative skeletal staining and quantification of WT and Wdr4R215L/R215L mouse limbs at P0. n = 8 for WT and n = 6 for Wdr4R215L/R215L. (E) Representative Alcian blue/von Kossa staining of WT and Wdr4R215L/R215L mouse femurs at P0. Scale bar: 200 μm. (F and G) Representative immunostaining and quantification of Col10 and MMP13 of WT and Wdr4R215L/R215L femora at P10. Scale bars: 200 μm. (H and I) Representative EdU labeling and quantification of WT and Wdr4R215L/R215L mouse femur at P7. Boxed areas are magnified. Scale bar: 200 μm. (J and K) Representative μCT images of femoral trabecular bone (top) and cortical bone (bottom) and related quantification from WT and Wdr4R215L/R215L mice at 6 weeks of age. BMD, bone mineral density; BV/TV, trabecular bone volume per tissue volume; Tb.Th, trabecular thickness; Tb.N, trabecular number; Tb.Sp, trabecular bone separation; Ct.Th, cortical bone thickness. Scale bars: 400 μm. n = 8. (L) Representative H&E staining of WT and Wdr4R215L/R215L mouse femur at 6 weeks of age. Scale bar: 200 μm. (M) Quantification of osteoblast numbers per bone perimeter (N.Ob/B.Pm). n = 8. (N) Quantification of osteoclast numbers per bone perimeter (N.Oc/B.Pm). n = 8. Data are expressed as mean ± SEM; *P < 0.05, **P < 0.01, ***P < 0.001 by 2-tailed Student’s t test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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