Glucocorticoids Inhibit BMSC Homing by Upregulating PPARγ through Genomic Pathways

Tao Lin, Lianping Wan, Zemiao Liu

Article ID: 8142
Vol 38, Issue 6, 2024
DOI: https://doi.org/10.23812/j.biol.regul.homeost.agents.20243806.410
Received: 12 September 2023; Accepted: 12 September 2023; Available online: 20 June 2024; Issue release: 20 June 2024


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Abstract

Background: In the context of glucocorticoid-induced femoral head necrosis, the overexpression of peroxisome proliferator-activated receptor γ (PPARγ), induced by glucocorticoid (GC), inhibits adipogenesis and promotes osteogenesis. Some studies have found that the stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) pathway mediates the homing of bone marrow mesenchymal stem cells (BMSCs). However, the mechanism of BMSCs homing regulated by GC is not fully understood. In this study, we aim to investigate the mechanism of how GC regulates BMSCs homing through PPARγ from the glucocorticoid receptors (GR) downstream, based on the regulatory signal ahead of the CXCR4. Methods: BMSCs were cultured, dexamethasone (DXMS) was applied to intervene the BMSCs, and the expression sites of GRα, PPARγ and CXCR4 were detected by immunofluorescence. The expression changes of cytokines GRα, PPARγ and CXCR4 after cell intervention were detected by quantitative real time polymerase chain reaction (qRT-PCR) and Western blot (WB) to explore cellular chemokines and their signaling pathways. Results: DXMS enhanced the expression of PPARγ and inhibited the expression of SDF-1 and CXCR4. The results revealed that the G protein-coupled receptor was involved in DXMS-regulated expression of SDF-1 and CXCR4, but did not play a major role, and this effect was GR dependent. The Western blot results showed that the downstream SDF-1/CXCR4 was significantly enhanced after GR silencing, suggesting that GR was involved in the BMSCs homing (p < 0.05). After DXMS treatment, the expression of SDF-1 and CXCR4 in BMSCs was inhibited, while PPARγ expression was significantly increased (p < 0.05). The fluorescence quantitation and the Western blot results showed a significant increase in the expression of SDF-1 and CXCR4 after PPARγ silencing (p < 0.05), suggesting the involvement of PPARγ in the expression of BMSCs. No significant change was observed in GR expression when PPARγ was inhibited, suggesting that GR is located in upstream of PPARγ. Additionally, the expression of SDF-1 and CXCR4 decreased significantly upon the addition of DXMS (p < 0.05). The inhibition of SDF-1 and CXCR4 by PPARγ is not complete, indicating the existence of other regulatory mechanisms. The PPARγ gene plays a crucial regulatory role in the DXMS-regulated expression of SDF-1 and CXCR4. Conclusions: DXMS inhibited the homing of BMSCs by upregulating PPARγ through genomic pathways. PPARγ plays a significant regulatory role in the downregulated expression of SDF-1 and CXCR4.


Keywords

glucocorticoid osteonecrosis of femoral head;bone marrow mesenchymal stem cells (BMSCs);peroxisome proliferator-activated receptor γ (PPARγ);homing;genomic effect


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