SENP3 Knockdown in Mesenchymal Stem Cells Contributes to Osteoclastogenesis via GLI2/COX2 Signaling Pathway
10.13865/j.cnki.cjbmb.2025.05.1539
- VernacularTitle:小鼠间充质干细胞SENP3缺失通过GLI2/COX2信号通路促进破骨细胞形成
- Author:
Tian-Tian LI
1
;
Zhi-Qiang LIU
Author Information
1. 天津医科大学基础医学院生理学与病理生理学系,天津 300070
- Publication Type:Journal Article
- Keywords:
mesenchymal stem cells(MSCs);
osteoclasts;
SUMO-specific protease 3(SENP3);
cy-clooxygenase-2(COX2);
glioma-associated oncogene homolog 2(Gli2);
E-type prostanoid receptor 4(EP4)
- From:
Chinese Journal of Biochemistry and Molecular Biology
2025;41(6):862-870
- CountryChina
- Language:Chinese
-
Abstract:
Mesenchymal stem cells(MSCs)induces fusion of multiple monocyte macrophages by secre-ting key cytokines such as receptor activator for nuclear factor-κB ligand(RANKL)and macrophage CSF(M-CSF)to form multinucleated macrophages thereby SUMO-specific protease 3(SENP3)modifies pro-teins by de-SUMOylation,which in turn affects the stability,localization and activity of substrate pro-teins.Based on the previous work in our laboratory,we found that the number of osteoclasts increased in mice with SENP3 knockdown in MSC(***P＜0.001).To further explore the mechanism,using immuno-fluorescence as well as Western blotting assay,we found that knockdown of the Hedgehog(Hh)signaling pathway by SENP3 increased the transcription factor glioma-associated oncogene homolog 2(Gli2),which is the most important transcription factor for the production of osteoclasts.CHIP-qPCR results showed that Gli2 promoted COX2 transcription by binding to cyclooxygenase-2(COX2)promoter regions-1 235～-1 249 and-1 158～-1 172(*P＜0.05);meanwhile,the main secretion product of COX2,pep-tide,was detected by ELISA(*P＜0.05).The level of prostaglandin E2(PGE2),the main secretory product of COX2,was increased in the supernatant of the culture medium of MSC with knockdown of SENP3 by ELISA(***P＜0.001).PGE2 is known to mediate cell migration and osteoclastogenesis through E-type prostanoid receptor 2(EP2)and E-type prostanoid receptor 4(EP4).In the study,the expression of EP4 receptor was found to be elevated in differentiated osteoclasts(**P＜0.01).The inhib-itors of the EP4 receptor significantly reduced the expression of nuclear factor-activated T cell 1(NFATc1),Cathepsin K(Ctsk),and tartrate resistant acid phosphatase(TRAP)genes(*P＜0.05)and decreased osteoclastogenesis(***P＜0.001),suggesting that EP4 receptors play a critical role in PGE2-mediated osteoclast differentiation.In conclusion,SENP3 deletion in mouse MSCs promotes COX2 transcription and PGE2 secretion through activation of the Hh signaling pathway thereby promoting osteo-clast formation.
