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This study focuses on the molecular mechanisms of bone insulin signaling regulation and insulin resistance. Addressing the current lack of global understanding of bone insulin signaling and the unclear differences in gene-specific activated signals under aging and insulin resistance conditions, through phosphorylationomics and functional genomic screening, the core regulatory factor AFF4 was identified. The key role of its P70S6K-dependent phosphorylation in bone insulin transcriptional regulation was elucidated, and the transcriptional abnormality mechanism of insulin-resistant bones in the elderly was revealed.
This review addresses the regeneration and repair dilemma caused by the heterogeneity of bone cartilage tissue, with the tissue engineering system combining mesenchymal stem cells and biomaterial scaffolds as the core. The regulatory mechanism of biological physical signals on stem cell fate is clarified, and the progress in the design of biomimetic microenvironment scaffolds guided by mechanical biology is systematically summarized. The precise regulation of mesenchymal stem cell lineage-specific differentiation is achieved, providing theoretical support and design references for layered bone cartilage regeneration, especially for the regeneration of subchondral bone.
01 Research Background
This study focuses on the molecular mechanisms of bone insulin signaling regulation and insulin resistance. Addressing the current lack of global understanding of bone insulin signaling and the unclear differences in gene-specific activated signals under aging and insulin resistance conditions, through phosphorylationomics and functional genomic screening, the core regulatory factor AFF4 was identified. The key role of its P70S6K-dependent phosphorylation in bone insulin transcriptional regulation was elucidated, and the transcriptional abnormality mechanism of insulin-resistant bones in the elderly was revealed.
The tendon-bone transition tissue has a highly specialized extracellular matrix structure, with the core feature being the hierarchical arrangement of collagen and the gradient composition of minerals. This structural system can achieve stable force transmission and play a directional guiding role in the cell phenotype of spatial organization. Currently, it is impossible to precisely reproduce the complex multi-scale structure and composition gradient at the tendon-bone interface, which has become a key bottleneck hindering the integration and regeneration of soft and hard tissue interfaces. It is urgently necessary to develop biomimetic matrix construction schemes that conform to the natural structure characteristics.
02 Main Content
The study compared the bone phosphorylationomics of young insulin-sensitive mice and elderly obese insulin-resistant mice, analyzed the reprogramming characteristics of insulin signaling; combined with zebrafish functional genomic screening, identified key phosphoproteins related to bone development and mineralization; targeted the core candidate gene AFF4, verified its insulin-dependent phosphorylation at specific sites and its abnormal changes in insulin-resistant bones, and elucidated the molecular mechanism of this phosphorylation-mediated gene-specific transcriptional activation.
03 Research Design
1. Animal model comparison: Select young insulin-sensitive mice and elderly obese insulin-resistant mice, extract bones for insulin signaling phosphorylationomics analysis, and compare the differences in phosphorylation modifications between the two groups;
2. Zebrafish functional screening: Use the zebrafish model for functional genomic screening to locate dysregulated phosphoproteins related to bone development and mineralization, and screen for core candidate genes;
3. Molecular mechanism verification: Verify the kinase-dependent phosphorylation of AFF4 at specific sites in osteoblasts, and analyze its regulatory effects on transcription elongation and recruitment of chromatin remodeling factors.
04 Results
1. Phosphorylationomics analysis revealed that the insulin signaling in the bones of elderly insulin-resistant mice had reconnected phosphorylation modifications, which were significantly different from those of young sensitive mice;
2. Zebrafish screening identified AFF4 as a key regulatory factor for bone formation, and its specific site is the insulin-dependent phosphorylation site mediated by P70S6K, and this site phosphorylation was significantly weakened in insulin-resistant bones of the elderly;
3. In insulin-resistant osteoblasts, the phosphorylation of AFF4 at this site was defective, leading to a decrease in the transcription elongation level at the specific genomic site. 4. Mechanically, the phosphorylation of this site in AFF4 can promote chromatin remodeling factors to bind to the vinylylated histone through specific domains, thereby achieving gene-specific transcriptional activation.
05 Extension of the idea
This study provides a new core target for the transcriptional regulation of the skeletal insulin signal. Further exploration can be conducted to investigate the regulatory patterns of AFF4 phosphorylation in different physiological and pathological skeletal states, deepen the research on the association between chromatin remodeling and gene-specific transcription, and expand the basic research direction of cross-regulation between bone metabolism and systemic energy metabolism.
Original source:
1. Journal: Nature Communications
2. Publication date: December 31, 2025
3. DOI: 10.1038/s41467-025-68106-4
4. Authors: Mriga Dutt et al. (team from the University of Melbourne and other institutions)
