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Published on: June 10, 2014
Mechanistic insights into Strontium-90 superficial radiotherapy in keloids: senescence-associated changes and ECM
Fushi Han1, Shengnan Ren1, Xiaoran Mei1
1Department of Nuclear Medicine, Shanghai Fourth People's Hospital Affiliated to Tongji University, Shanghai, China.
Background:
The limited efficacy of current keloid therapies necessitates a deeper understanding of treatment mechanisms. This study investigates the therapeutic potential and underlying pharmacological actions of strontium-90 (Sr-90) superficial radiotherapy, evaluating a dual-component antifibrotic working model.
Methods:
The effects of Sr-90 irradiation were studied in primary keloid fibroblasts and a rabbit ear scar model. We assessed cell proliferation, migration, senescence (SA-β-gal), and DNA damage. Molecular profiling (Western blot, RT-qPCR, enzymatic assays) evaluated the p53-p21-DNA damage response axis and lysyl oxidase (LOX/LOXL2) pathway. Transcriptomic analysis (RNA-seq) with GO/KEGG enrichment was performed. Collagen ultrastructure and crosslinking-related indices were analyzed, alongside tissue remodeling evaluated by multimodal imaging optical coherence tomography and biomechanics (nanoindentation). Functional validation used Pifithrin-α and β-aminopropionitrile (BAPN).
Results:
Sr-90 irradiation was accompanied by activation of the p53-p21-DDR pathway, increased senescence-associated features, and reduced fibroblast proliferation and migration. Concurrently, it suppressed LOX/LOXL2 expression and activity, accompanied by changes in collagen crosslinking-related indices and improved tissue elasticity. Transcriptomics revealed downregulation of genes in extracellular matrix (ECM) organization, focal adhesion, and PI3K-Akt signaling. These changes were accompanied by reduced collagen deposition, disassembly of the collagen network, decreased fibrotic thickness, and restoration of tissue mechanical properties. P53 pathway inhibition attenuated these effects, whereas LOX inhibition further enhanced the matrix-remodeling response. Animal findings were generally consistent with the in vitro observations.
Conclusion:
Sr-90 irradiation was associated with fibroblast senescence and accompanying p53-p21-DDR activation, together with reduced LOX/LOXL2 expression and activity, which may contribute to attenuation of collagen crosslinking-related matrix stabilization. These parallel cellular and matrix-associated changes may jointly promote scar remodeling by affecting both fibroblast behavior and ECM architecture. These findings provide preliminary mechanistic support for further investigation of Sr-90 superficial radiotherapy and matrix-targeted combination strategies in keloid fibrosis.
