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Tumor Necrosis Factor Alpha-Induced Protein 6 Suppresses Inflammation and Promotes Osteogenesis via Type H Vessels in
Yao-Wen Zhang1, Sheng-Tao Zhao1, Zi-Jian Zhang1
1Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology & Department of Periodontology, Shanghai Tongji Stomatological Hospital and Dental School, Tongji University, Shanghai, P. R. China.
Aim:
To investigate the impact of tumor necrosis factor (TNF)-α-stimulated gene 6 (TSG-6) on inflammation, type H vessel formation, and coupled osteogenesis in periodontitis.
Methods:
Gingival tissues (n = 10 per group) and gingival crevicular fluid (GCF) samples (n = 12 per group) were collected from periodontitis patients and healthy controls. Human periodontal ligament cells (HPDLCs) were used to evaluate the effect of TSG-6 on cell function, mitochondrial homeostasis, and the cGAS-STING pathway activation. Human umbilical vein endothelial cells (HUVECs) and mouse bone marrow stem cells (mBMSCs) were employed to further validate TSG-6's impact on angiogenesis and osteogenesis under periodontitis microenvironments. C57BL/6 mice were utilized to establish a ligature-induced periodontitis model. RNA sequencing, quantitative reverse transcription PCR, immunohistochemistry, immunofluorescence staining, enzyme-linked immunosorbent assays, micro-computed tomography, and western blotting were conducted to explore the involvement of TSG-6 in periodontitis and its underlying mechanism.
Results:
The expression of TSG-6 was upregulated in the gingival tissues and GCF samples affected by periodontitis compared to that in healthy controls. TSG-6 restored cell functions, alleviated inflammation, and promoted osteogenesis in lipopolysaccharide (LPS)-induced HPDLCs via maintaining mitochondrial homeostasis and inhibiting cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway activation. Furthermore, local injection of TSG-6 effectively suppressed inflammation and attenuated bone resorption while stimulating type H vessel formation and coupled osteoprogenitor expression by reducing CXC-chemokine ligand (CXCL)-9 secretion.
Conclusion:
TSG-6 suppresses inflammation and attenuates bone resorption while stimulating type H vessel formation and coupled bone regeneration in periodontitis via reducing mitochondrial damage, inhibiting cGAS-STING pathway activation, and subsequent CXCL-9 secretion.
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