Molecular mechanism of extracellular matrix disorder in pelvic organ prolapses

Zhang, Liping; Dai, Fangfang; Chen, Gantao; Wang, Yanqing; Liu, Shiyi; Zhang, Li; Shu, Xian; Yuan, Mengqin; Yang, Dongyong; Zheng, Y.; Deng, Zhanfeng; Cheng, Yanxiang; Yang, Xiaofeng

doi:10.3892/mmr.2020.11564

Cited by 16 publications

(13 citation statements)

References 40 publications

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“…Fibroblasts are responsible for the secretion and remodeling of ECM in ECM-rich pelvic connective tissues that primarily support the pelvic organs. The disfunction of fibroblasts resulted in a disordered metabolism of collagen and other ECM proteins (40)(41)(42). Therefore, the increased fibroblast apoptosis could result in reduced collagen expression in POP and contribute to the weakness of supportive tissues in POP (40,43).…”

Section: Discussionmentioning

confidence: 99%

Advanced glycation end products (AGEs) downregulate the miR-4429/PTEN axis to promote apoptosis of fibroblasts in pelvic organ prolapse

Sima¹,

Li²,

Xiao³

et al. 2022

Ann Transl Med

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Background: Pelvic organ prolapse (POP) is a common degenerative disease among females. We previously reported that advanced glycation end products (AGEs), compounds derived from nonenzymatic glycoxidation reactions, accumulated in the human vaginal wall and impaired the function of fibroblasts in the pathogenesis of POP. This study investigated the apoptosis induced by AGEs in human uterosacral ligament fibroblasts and the underlying mechanism.Methods: Human uterosacral ligament fibroblasts were cultured and identified. Quantitative real-time polymerase chain reaction (Qrt-PCR) analysis was performed to identify the expression of miR-4429, phosphatase and tensin homolog (PTEN), and caspase-3. Flow cytometric analysis was applied to detect the apoptosis rate of fibroblasts. Dual-luciferase reporter assay was performed to verify the relationship between miR-4429 and PTEN. The overexpression of miR-4429 and the inhibition of PTEN were achieved by cell transfections. Western blot analysis was used to detect the protein levels of PTEN, phosphoinositide 3-kinase (PI3K), and protein kinase B (Akt). Results:The AGEs promoted fibroblast apoptosis both in the POP and the non-POP groups. The expression of PTEN increased in fibroblasts from the POP group or fibroblasts treated with AGEs. It was confirmed that miR-4429 interacted with PTEN messenger RNA (mRNA), and the expression level of miR-4429 was reduced in fibroblasts from the POP group or fibroblasts treated with AGEs. Further, overexpression of miR-4429 alleviated increased PTEN expression and fibroblast apoptosis induced by AGEs. Similarly, inhibition of PTEN expression alleviated increased fibroblast apoptosis induced by AGEs. In addition, the protein expressions of PI3K and phosphorylated Akt were reduced in fibroblasts exposed to AGEs. Conclusions:We proposed that AGEs induced fibroblast apoptosis by regulating the miR-4429/PTEN/ PI3K/Akt pathway in POP. Our results revealed a novel mechanism by which AGEs contributed to the molecular pathological alteration in POP.

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Section: Discussionmentioning

confidence: 99%

Advanced glycation end products (AGEs) downregulate the miR-4429/PTEN axis to promote apoptosis of fibroblasts in pelvic organ prolapse

Sima¹,

Li²,

Xiao³

et al. 2022

Ann Transl Med

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“…The above findings suggest that HOXA11 and TGF-β1 exert a synergistic effect on the expression of collagen and MMP enzymes. These two signaling mediators have important roles in the development of ECM, as demonstrated by a recent study (18). The balanced turnover of collagen is necessary for maintaining the mechanical strength of pelvic supportive connective tissues.…”

Section: Mechanisms Underlying Popmentioning

confidence: 94%

“…The major components of ECM are elastic fibers and collagen. Elastic fibers are able to maintain the integrity of pelvic organs and vaginal structures to resist mechanical strain due to its elasticity and recoil properties (18). Patients with POP exhibit weakened flexibility of elastin and increased flexibility of elastase, which disrupts the mechanical balance of the pelvic floor (19).…”

Section: Mechanisms Underlying Popmentioning

confidence: 99%

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Advances in molecular mechanisms of pelvic organ prolapse (Review)

et al. 2021

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Pelvic organ prolapse (POP) is a common gynecological benign disease occurring in middle-aged and elderly females. Its incidence increases every year. To date, the majority of studies investigating its etiology have not evaluated the underlying molecular mechanisms, which has caused substantial difficulties in the prevention, treatment and prognosis of POP. In the present narrative review, recent research studies concerning the molecular mechanisms of POP were systematically reviewed and the advances were summarized. The association between the incidence of POP and the reduction of the extracellular matrix, activation of oxidative stress, genetic susceptibility, denervation of the pelvic floor and reduction of estrogen infiltration were explored. POP is mainly associated with damage of pelvic floor muscles and connective tissue, which are directly caused by pregnancy and vaginal delivery. The majority of the molecular and genetic mutations associated with POP involve specific components of connective tissue synthesis and degradation. It is likely that macroscopic parameters, such as anatomy, lifestyle and reproductive factors, interact with microscopic parameters, such as physiology and genetics in the female pelvic floor, leading to POP. Additional research studies investigating the molecular mechanisms of POP should be performed, since they may aid public health strategies. In the present narrative review, a summary of these molecular mechanisms underlying the development of POP is provided. This included the relevant proteins and genes involved. On this basis, countermeasures were proposed. Contents

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“…Fibroblasts isolated from the uterosacral ligaments or vaginal wall have been intensively investigated to elucidate the pathophysiology of POP. Pathological changes in fibroblasts, such as an increase in intracellular reactive oxygen species and abnormal ECM production, have been observed under the mechanical stress of POP (7)(8)(9)(10). Fibroblasts are recognized as a heterogeneous population of cells in several organs and tissues (11).…”

Section: Introductionmentioning

confidence: 99%

CD106/VCAM-1 distinguishes a fibroblast subpopulation with high colony-forming capacity and distinct protein expression from the uterosacral ligament

Sima

Xiao

et al. 2022

Ann Transl Med

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Background Pelvic organ prolapse (POP) is a common degenerative disease in women which may diminish quality of life. Investigating the pathological changes of the uterosacral ligament, including the functional changes of fibroblasts, is critical to understanding the pathophysiology of POP. This study was designed to isolate CD106-positive (CD106 + ) fibroblasts from the human uterosacral ligament and assess the function and expression of this subpopulation. Methods We separated CD106 + fibroblasts and CD106 negative (CD106 − ) fibroblasts by fluorescence-activated cell sorting (FACS) and cultured them for subsequent experiments. Flow cytometric analysis was used to test the sorting efficiency, CD106 expression, and typical mesenchymal stem cell (MSC) phenotype marker expression. A colony-forming unit (CFU) assay was applied to evaluate the colony-forming ability of the fibroblasts. Trilineage differentiation capacities were assessed after in vitro induction. The protein levels of vimentin, fibroblast specific protein-1 (FSP-1), collagen I (COL 1), matrix metallopeptidase-1 (MMP-1), and α-smooth muscle actin (α-SMA) were detected by western blot analysis. The expression of CD106 was verified by flow cytometric analysis and immunohistochemistry (IHC) in the POP and non-POP groups. Results The CD106 + fibroblasts were isolated with a purity of (93.50±3.91)%. The CD106 + fibroblasts exhibited higher colony-forming capacity than that of CD106 − fibroblasts, but neither of them showed adipogenic or osteogenic differentiation similar to that of MSCs. The protein levels of MMP-1 and α-SMA were lower, and the level of COL 1 was higher in the CD106 + fibroblasts than in the CD106− fibroblasts. In addition, we observed a decreased expression of CD106 in the POP group compared with the non-POP group. Conclusions Our results suggest that CD106 + fibroblasts possess a high colony-forming capacity and distinct protein expression, and this subpopulation is reduced in POP.

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Molecular mechanism of extracellular matrix disorder in pelvic organ prolapses

Cited by 16 publications

References 40 publications

Advanced glycation end products (AGEs) downregulate the miR-4429/PTEN axis to promote apoptosis of fibroblasts in pelvic organ prolapse

Advanced glycation end products (AGEs) downregulate the miR-4429/PTEN axis to promote apoptosis of fibroblasts in pelvic organ prolapse

Advances in molecular mechanisms of pelvic organ prolapse (Review)

CD106/VCAM-1 distinguishes a fibroblast subpopulation with high colony-forming capacity and distinct protein expression from the uterosacral ligament

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