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This study clearly demonstrates that the deficiency of SMN promotes the ubiquitination and degradation of YBX1 mediated by TRAF6, thereby inhibiting endochondral ossification in spinal muscular atrophy, revealing the core regulatory role of SMN in chondrocyte differentiation and skeletal development.
01 Research Background
The SMN protein is encoded by the SMN1 gene and is widely expressed and essential for the body; previous studies have confirmed that SMN deficiency impairs skeletal development, but the molecular mechanism of abnormal cartilage ossification has not been clearly resolved.
02 Main Content
This study explores the molecular mechanism by which SMN deficiency affects skeletal development in spinal muscular atrophy models, focusing on hypertrophic chondrocyte differentiation, RNA splicing, and protein degradation regulation, and elucidates the regulatory effect of the SMN-TRAF6-YBX1 axis on endochondral ossification.
03 Research Design
Combining single-cell RNA sequencing, transcriptome sequencing, and mass spectrometry proteomics analysis, we constructed SMA mouse models and chondrocyte condition knockdown/overexpression mouse models, supplemented with histological analysis, molecular interaction, and ubiquitination detection experiments.
04 Results
SMN deficiency causes dwarfism and delayed cartilage ossification in model mice; SMN deficiency expands the hypertrophic chondrocyte area in the growth plate and delays the transition from hypertrophy to ossification; the chondrocytes of the growth plate in SMA mice show extensive changes in the expression and alternative splicing of genes related to endochondral ossification; SMN deficiency leads to a decrease in YBX1 protein levels, and knockdown of YBX1 can reproduce the abnormal gene expression and splicing characteristics of the cartilage in SMA; TRAF6 mediates the ubiquitination and degradation of YBX1, and this pathway is regulated by SMN; the expression of SMN in chondrocytes is the key for hypertrophic chondrocytes to mediate endochondral ossification.
05 Extension of Thoughts
Focusing on the SMN-TRAF6-YBX1 regulatory axis, we explore its role in other skeletal developmental disorders; deeply analyze the synergistic regulatory mode of SMN on RNA splicing and protein degradation, and improve the molecular regulatory network of skeletal development; explore potential molecular targets that regulate endochondral ossification in this pathway.
Original Source:
1. Journal: Bone Research
2. Publication Date: December 12, 2025
3. DOI: 10.1038/s41413-025-00473-6
4. Authors: Zijie Zhou, Xinbin Fan, Taiyang Xiang, Yinxuan Suo, Xiaoyan Shi, Yaoyao Li, Yimin Hua, Lei Sheng, Xiaozhong Zhou
