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α-Asarone promotes tendon-bone healing through regulating Dmp1 transcription via targeting transcription factor PPARG

ABSTRACT: Background: The tendon-bone interface (TBI) frequently proves refractory to restoration following surgical reconstruction or even surgical failure, due to the intricate nature of its structure. α-Asarone (αASA), an active ingredient derived from the traditional Chinese medicinal plant Calamus, has been demonstrated to possess beneficial effects in the treatment of inflammatory and osteoporotic conditions. However, its impact on TBI has yet to be investigated. Objective: This study aimed to elucidate the therapeutic effects of αASA on TBI in vivo and in vitro, gain insight into the underlying mechanisms involved, and assess its potential medicinal value in humans. Methods: A mouse model and a cellular model of tendon-bone interface (TBI) healing were developed. The impact of αASA on TBI was investigated at both the in vitro and vivo levels through a range of techniques, including protein gene assays, cell staining, biomechanics, imaging, and histology. Concurrently, network pharmacology, transcriptomics, molecular docking, transcription factor prediction, and experimental validation were employed to conduct a comprehensive investigation of its specific effects and mechanism of action. Subsequently, In addition, the clinical medicinal value of αASA was validated by human BMSCs (hBMSCs). Results: In vivo, αASA treatment enhanced the biomechanical properties and osseointegration of tendon-bone samples in mice. In vitro, αASA promoted osteogenic differentiation of BMSCs, as evidenced by staining and the expression of osteogenic marker genes. Using network pharmacology, we identified 29 core co-target genes of αASA in the treatment of TBI. The top 20 differentially expressed genes (DEGs) underwent GO, KEGG, and GSEA enrichment analyses, revealing their involvement in tissue mineralization and ossification processes. Additionally, 207 transcription factors (TFs) were predicted for these DEGs, with 9 identified as core co-target genes. Surface plasmon resonance (SPR) confirmed the strong affinity of αASA for the transcription factor PPARG, while luciferase assays demonstrated PPARG binding to the Dmp1 promoter to regulate transcription. αASA also enhanced osteogenic differentiation in human BMSCs, supporting its potential for clinical application. Conclusion: αASA promotes osteogenic differentiation and improves TBI healing in mBMSCs by targeting and down-regulating the transcription factor PPARG to inhibit its binding to the Dmp1 promoter, while exerting the same effect in hBMSCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE278394 | GEO | 2025/09/30

REPOSITORIES: GEO

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Project description:The treatment of bone defects caused by infection, trauma or neoplasms remains a clinical challenge. Autologous bone transplantation is limited by availability, donor site morbidity and surgical risk factors. This has given rise to stromal/stem-cell based therapy. Bone marrow derived stromal cells (BMSCs) have been studied to a large extent and show high regenerative potential but their use is limited by availability, donor site morbidity and the relatively low cell yield as they represent only <0.1% of cell harvested from bone marrow aspirate. At the same time, they are the closest mesenchymal stromal cells for bone tissue engineering given their tissue origin and, unlike other mesenchymal stromal cells, can support the formation of hematopoietic marrow. Adipose tissue derived stromal cells (ASCs) as part of the stromal vascular fraction of adipose tissue can as well undergo osteogenic differentiation but can be additionally isolated in a sufficient quantity from lipoaspirate after liposuction of abundant subcutaneous fat tissue. Here, it has been shown that there are no major differences in regard to proliferation or differentiation capacity of ASCs derived from subcutaneous fat of different anatomical regions. It has been shown that BMSCs are more prone to senescence during expansion and passage than ASCs and that ageing impacts proliferative capabilities of BMSCs more than that of ASCs while it has also been reported that osteogenic differentiation capacity is least impacted by age. Multiple studies have compared the characteristics of these two mesenchymal stromal cells in regard to bone tissue engineering in vitro. Most studies point to inferior extracellular matrix mineralization and lower expression of key osteogenic transcription markers like Runx2 in osteogenic differentiated ASCs compared to BMSCs. On the other hand, a study by Rath et al. found contrary results using particular culturing conditions like 3D bioglass scaffolds. An intraindividual comparison of human MSCs of three donors cultured on decellularized porcine bone confirmed superior osteogenic capacity of BMSCs compared to ASCs. In contrast to BMSCs, ASCs were not able to induce heterogenic ossification in a mouse model. In a sheep tibia defect model application of BMSCs resulted in a significantly higher amount of newly formed bone tissue. Importantly, Osteogenic differentiated ASCs do not support the formation of a hematopoietic marrow. Proteomics enables large-scale analysis of proteins present in a cell type and can be used to identify differentially regulated key proteins in a comparative approach. A comparative proteomic analysis of BMSCs and ASCs by Roche et al. in 2009 identified 556 proteins with 78% of these not being differentially regulated between these two cell populations, regarded as high similarity. Another comparative proteomic study of 2016 by Jeon et al. found 90 differentially regulated proteins out of 3000 total identified proteins. Both studies do not specify a number of different tissue donors and in part using cell lines. Looking for differences upon osteogenic differentiation, transcriptomic comparison of osteogenic differentiated porcine ASCs and BMSCs has been performed, resulting in 21 differentially expressed genes after 21 days of osteogenic culture conditions. Still, it remains unanswered, which are the key distinctive features of osteogenic differentiated ASCs and BMSCs at protein level that might help address the abovementioned weaknesses of ASCs in bone tissue engineering/regeneration for translational research. To overcome this need, an intraindividual comparative DIA based proteomic analysis of osteogenic differentiated human BMSC and ASCs was performed in this study.

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α-Asarone promotes tendon-bone healing through regulating Dmp1 transcription via targeting transcription factor PPARG

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