title: Collagen metabolic disorder induced by oxidative stress in human uterosacral ligament‑derived fibroblasts: A possible pathophysiological mechanism in pelvic organ prolapse.
abstract: Pelvic organ prolapse (POP) is a global health problem, for which the pathophysiological mechanism remains to be fully elucidated. The loss of extracellular matrix protein has been considered to be the most important molecular basis facilitating the development of POP. Oxidative stress (OS) is a well‑recognized mechanism involved in fiber metabolic disorders. The present study aimed to clarify whether OS exists in the uterosacral ligament (USL) with POP, and to investigate the precise role of OS in collagen metabolism in human USL fibroblasts (hUSLFs). In the present study, 8‑hydroxyguanosine (8‑OHdG) and 4 hydroxynonenal (4‑HNE), as oxidative biomarkers, were examined by immunohistochemistry to evaluate oxidative injury in USL sections in POP (n=20) and non‑POP (n=20) groups. The primary cultured hUSLFs were treated with exogenous H2O2 to establish an original OS cell model, in which the expression levels of collagen, type 1, α1 (COL1A1), matrix metalloproteinase (MMP)‑2, tissue inhibitor of metalloproteinase (TIMP)‑2 and transforming growth factor (TGF)‑β1 were evaluated by western blot and reverse transcription‑quantitative polymerase chain reaction analyses. The results showed that the expression levels of 8‑OHdG and 4‑HNE in the POP group were significantly higher, compared with those in the control group. Collagen metabolism was regulated by H2O2 exposure in a concentration‑dependent manner, in which lower concentrations of H2O2 (0.1‑0.2 mM) stimulated the anabolism of COL1A1, whereas a higher concentration (0.4 mM) promoted catabolism. The expression levels of MMP‑2, TIMP‑2 and TGF‑β1 exhibited corresponding changes with the OS levels. These results suggested that OS may be involved in the pathophysiology of POP by contributing to collagen metabolic disorder in a severity‑dependent manner in hUSLFs, possibly through the regulation of MMPs, TIMPs and TGF‑β1 indirectly.
authors.affiliation: Department of Gynecology and Obstetrics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Gynecology and Obstetrics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Gynecology and Obstetrics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
authors.forename: Gui
authors.initials: G
authors.lastname: Fang
authors.affiliation: Department of Gynecology and Obstetrics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
authors.forename: Bing-Shu
authors.initials: BS
authors.lastname: Li
authors.affiliation: Department of Gynecology and Obstetrics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
authors.forename: De-Bin
authors.initials: DB
authors.lastname: Wu
authors.affiliation: Department of Gynecology and Obstetrics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Guo
authors.affiliation: Department of Gynecology and Obstetrics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
authors.forename: Sha-Sha
authors.initials: SS
authors.lastname: Hong
authors.affiliation: Department of Gynecology and Obstetrics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Hong
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D016022:Case-Control Studies; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006151:Guanosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D007150:Immunohistochemistry; D008022:Ligaments / Q000166:cytology*; D008875:Middle Aged; D018384:Oxidative Stress; D056887:Pelvic Organ Prolapse / Q000378:metabolism* / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D015415:Biomarkers; D017382:Reactive Oxygen Species; D006151:Guanosine; C046215:8-hydroxyguanosine; D003094:Collagen; D006861:Hydrogen Peroxide