Mast cell tryptase-PAR2 axis promotes ovarian fibrosis through RNF152-mediated stabilization of Bcl-xL.
Abstract Background Our research aimed to study the effect and mechanism of tryptase on ovarian fibrosis. Methods The POI mouse model was established by cisplatin at a dose of 1.5 mg/kg for ten days, while the control mice were given the same volume of saline. C57BL/6 female mice were intraperitonea...
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BMC
2025-06-01
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| Series: | Journal of Ovarian Research |
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| Online Access: | https://doi.org/10.1186/s13048-025-01704-4 |
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| author | Xiang Zhang Jun Zhang Chaojun Wang |
| author_facet | Xiang Zhang Jun Zhang Chaojun Wang |
| author_sort | Xiang Zhang |
| collection | DOAJ |
| description | Abstract Background Our research aimed to study the effect and mechanism of tryptase on ovarian fibrosis. Methods The POI mouse model was established by cisplatin at a dose of 1.5 mg/kg for ten days, while the control mice were given the same volume of saline. C57BL/6 female mice were intraperitoneally injected with 10 mg/kg cromolyn (n = 20 per group) or sterile saline (n = 20 per group) at two days before cisplatin treatment to assess the effect of cromolyn sodium on ovarian function and fibrosis. The ovaries of each mouse were collected for histological examination and collagen levels analysis. The effects of mast cells and tryptase on collagen I protein expression were investigated in primary mouse ovarian theca-stroma cells in vitro. The levels of sex hormones and tryptase were determined by ELISA. Results Tryptase secreted by activated mast cells induced COL1A1 and COL1A2 production, two subunits of collagen I in mouse theca-stroma cells by protease-activated receptor-2 signaling. Inhibition of PAR2 or Bcl-xL attenuated the increases of COL1A1 and COL1A2 caused by tryptase. In addition, knockdown of RNF152 reversed the downregulation of collagen production caused by si-Bcl-xL. Clinically, tryptase levels in serum and follicular fluid were higher in both bPOI and POI patients than in controls. Tryptase concentrations in serum and follicular fluid were positively associated with follicle stimulating hormone (FSH) and negatively associated with anti-Müllerian hormone (AMH). Cromolyn sodium, a mast cell stabilizer, reduced collagen I production, but had no effect on hormone synthesis and follicle number in a cisplatin-induced POI mouse model. Conclusions Tryptase might be associated with the pathogenesis of cisplatin-induced POI by promoting ovarian fibrosis through PAR2 via stabilization of Bcl-xL. |
| format | Article |
| id | doaj-art-940bb65a771043aba06b7ae0ae0e2a51 |
| institution | OA Journals |
| issn | 1757-2215 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
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| series | Journal of Ovarian Research |
| spelling | doaj-art-940bb65a771043aba06b7ae0ae0e2a512025-08-20T02:30:43ZengBMCJournal of Ovarian Research1757-22152025-06-0118111610.1186/s13048-025-01704-4Mast cell tryptase-PAR2 axis promotes ovarian fibrosis through RNF152-mediated stabilization of Bcl-xL.Xiang Zhang0Jun Zhang1Chaojun Wang2Department of Anesthesiology, Department of Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Fudan UniversityDepartment of Anesthesiology, Department of Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Fudan UniversityDepartment of Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityAbstract Background Our research aimed to study the effect and mechanism of tryptase on ovarian fibrosis. Methods The POI mouse model was established by cisplatin at a dose of 1.5 mg/kg for ten days, while the control mice were given the same volume of saline. C57BL/6 female mice were intraperitoneally injected with 10 mg/kg cromolyn (n = 20 per group) or sterile saline (n = 20 per group) at two days before cisplatin treatment to assess the effect of cromolyn sodium on ovarian function and fibrosis. The ovaries of each mouse were collected for histological examination and collagen levels analysis. The effects of mast cells and tryptase on collagen I protein expression were investigated in primary mouse ovarian theca-stroma cells in vitro. The levels of sex hormones and tryptase were determined by ELISA. Results Tryptase secreted by activated mast cells induced COL1A1 and COL1A2 production, two subunits of collagen I in mouse theca-stroma cells by protease-activated receptor-2 signaling. Inhibition of PAR2 or Bcl-xL attenuated the increases of COL1A1 and COL1A2 caused by tryptase. In addition, knockdown of RNF152 reversed the downregulation of collagen production caused by si-Bcl-xL. Clinically, tryptase levels in serum and follicular fluid were higher in both bPOI and POI patients than in controls. Tryptase concentrations in serum and follicular fluid were positively associated with follicle stimulating hormone (FSH) and negatively associated with anti-Müllerian hormone (AMH). Cromolyn sodium, a mast cell stabilizer, reduced collagen I production, but had no effect on hormone synthesis and follicle number in a cisplatin-induced POI mouse model. Conclusions Tryptase might be associated with the pathogenesis of cisplatin-induced POI by promoting ovarian fibrosis through PAR2 via stabilization of Bcl-xL.https://doi.org/10.1186/s13048-025-01704-4Premature ovarian insufficiencyMast cellTryptaseCollagen IPAR2Bcl-xL |
| spellingShingle | Xiang Zhang Jun Zhang Chaojun Wang Mast cell tryptase-PAR2 axis promotes ovarian fibrosis through RNF152-mediated stabilization of Bcl-xL. Journal of Ovarian Research Premature ovarian insufficiency Mast cell Tryptase Collagen I PAR2 Bcl-xL |
| title | Mast cell tryptase-PAR2 axis promotes ovarian fibrosis through RNF152-mediated stabilization of Bcl-xL. |
| title_full | Mast cell tryptase-PAR2 axis promotes ovarian fibrosis through RNF152-mediated stabilization of Bcl-xL. |
| title_fullStr | Mast cell tryptase-PAR2 axis promotes ovarian fibrosis through RNF152-mediated stabilization of Bcl-xL. |
| title_full_unstemmed | Mast cell tryptase-PAR2 axis promotes ovarian fibrosis through RNF152-mediated stabilization of Bcl-xL. |
| title_short | Mast cell tryptase-PAR2 axis promotes ovarian fibrosis through RNF152-mediated stabilization of Bcl-xL. |
| title_sort | mast cell tryptase par2 axis promotes ovarian fibrosis through rnf152 mediated stabilization of bcl xl |
| topic | Premature ovarian insufficiency Mast cell Tryptase Collagen I PAR2 Bcl-xL |
| url | https://doi.org/10.1186/s13048-025-01704-4 |
| work_keys_str_mv | AT xiangzhang mastcelltryptasepar2axispromotesovarianfibrosisthroughrnf152mediatedstabilizationofbclxl AT junzhang mastcelltryptasepar2axispromotesovarianfibrosisthroughrnf152mediatedstabilizationofbclxl AT chaojunwang mastcelltryptasepar2axispromotesovarianfibrosisthroughrnf152mediatedstabilizationofbclxl |