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image of Impact of All-trans Retinoic Acid on Skeletal Development: Mechanisms of Growth Plate Closure

Abstract

Introduction

All-trans retinoic acid (ATRA), a therapeutic mainstay for acute promyelocytic leukemia, is associated with off-target effects on skeletal development, including premature growth plate closure. However, the molecular mechanisms underlying ATRA-induced growth plate senescence remain poorly understood.

Methods

Using Sprague-Dawley rats, ADTC5 chondrocyte cell lines, and integrated multi-omics approaches (transcriptome sequencing, weighted gene co-expression network analysis, molecular docking, and functional assays), we investigated how ATRA modulates growth plate development. Animal models were treated with graded ATRA doses, while studies included cell viability assays, RNA interference, and Western blot analysis to validate interactions in the signaling pathway.

Results

ATRA induced dose-dependent growth plate thinning (high-dose: 59.79 µm . control: 511.35 µm) and skeletal growth retardation in rats. Transcriptomic analysis identified ITGB2 as a pivotal gene, with molecular docking revealing a strong binding interaction (-240.25 kcal/mol) between ITGB2 and YAP mediated by hydrogen bonds/salt bridges. Functional experiments revealed that ATRA upregulated ITGB2, which activated YAP, a Hippo pathway effector, thereby suppressing Wnt/β-catenin signaling by inhibiting β-catenin. This led to downregulation of osteogenic markers (Runx2/SOX9) and enhanced growth plate closure. YAP knockdown reversed these effects, restoring β-catenin and downstream target gene expression (c-myc, cyclin D).

Discussion

Collectively, our findings identify the ITGB2-YAP signaling axis as a novel mechanism underlying ATRA-induced growth plate closure. These findings establish a foundational framework for developing therapeutic strategies, such as targeting ITGB2 or YAP, to potentially delay premature growth plate closure in pediatric patients undergoing ATRA treatment or with related skeletal disorders.

Conclusion

ATRA accelerates growth plate closure through the ITGB2-YAP axis, disrupting Wnt/β-catenin signaling. These findings establish a mechanistic framework for developing therapeutic strategies targeting ITGB2 or YAP to delay premature growth plate senescence in pediatric disorders.

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2026-01-14
2026-01-29

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Impact of All-trans Retinoic Acid on Skeletal Development: Mechanisms of Growth Plate Closure
Bentham Science Publishers ; https://doi.org/10.2174/0113862073424590251103061707
/content/journals/cchts/10.2174/0113862073424590251103061707
/content/journals/cchts/10.2174/0113862073424590251103061707
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  • Article Type:     Research Article
Keywords: Wnt signaling pathway ; RNA ; Growth plate closure ; All-trans retinoic acid ; ITGB2 ; YAP

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