Decreased expression of elastin, fibulin‐5 and lysyl oxidase‐like 1 in the uterosacral ligaments of postmenopausal women with pelvic organ prolapse

Zhao, Baihui; Zhou, Jianhong

doi:10.1111/j.1447-0756.2011.01814.x

Cited by 51 publications

(41 citation statements)

References 25 publications

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“…10 Research with the Loxl1 KO mouse model in particular is supported by human genetic data implicating abnormal elastin homeostasis in the pathophysiology of POP. 14,28 In addition, POP in Loxl1 KO mice simulates the phenotype of POP in women, with vaginal delivery as a major risk factor, often affecting voiding function, and progressing with age. 1,11,12 …”

Section: Discussionmentioning

confidence: 99%

“…10 Although, no animal model is capable of incorporating all the characteristics and risk factors of POP in women, lysyl oxidase like-1 knockout ( Loxl1 KO) mice develop POP with phenotypic characteristics and risk factors similar to women, although they present a higher incidence of rectal prolapse than humans. 11–14 LOXL1 is a metalloenzyme responsible for crosslinking tropoelastin into its functional form, elastin, which provides the extracellular matrix (ECM) with its structure and recoil properties. 15 Similar to women, parity is the leading risk factor for POP in Loxl1 KO mice and POP is delayed, but not prevented, by cesarean delivery.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Pregnancy and Delivery on Cytokine Expression in a Mouse Model of Pelvic Organ Prolapse

Couri

Borazjani

Balog

et al. 2017

Female Pelvic Med Reconstr Surg

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Objectives The aim of this study was to determine the effect of pregnancy and delivery mode on cytokine expression in the pelvic organs and serum of lysyl oxidase like-1 knockout (Loxl1 KO) mice, which develop pelvic organ prolapse (POP) after delivery. Methods Bladder, urethra, vagina, rectum and blood were harvested from female Loxl1 KO mice during pregnancy, after vaginal or cesarean delivery, and from sham cesarean and unmanipulated controls. Pelvic organs and blood were also harvested from pregnant and vaginally delivered wild-type (WT) mice and from unmanipulated female virgin WT controls. Specimens were assessed using qRT-PCR and/or ELISA. Results Both Cxcl12 and Ccl7 mRNA were significantly upregulated in the vagina, urethra, bladder, and rectum of pregnant Loxl1 KO mice compared to pregnant WT mice, suggesting systemic dysregulation of both of these cytokines in Loxl1 KO mice as a response to pregnancy. The differences in cytokine expression between Loxl1 KO and WT mice in pregnancy persisted after vaginal delivery. Ccl7 gene expression increases faster and to a greater extent in Loxl1 KO mice, translating to longer lasting increases in CCL7 in serum of Loxl1 KO mice after vaginal delivery, compared to pregnant mice. Conclusions Loxl1 KO mice have an increased cytokine response to pregnancy, perhaps because they are less able to reform and re-crosslink stretched elastin to accommodate pups and this resultant tissue stretches during pregnancy. Upregulation of CCL7 after delivery could provide an indicator of level of childbirth injury, to which the urethra and vagina appear to be particularly vulnerable.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of Pregnancy and Delivery on Cytokine Expression in a Mouse Model of Pelvic Organ Prolapse

Couri

Borazjani

Balog

et al. 2017

Female Pelvic Med Reconstr Surg

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“…LOXL1-deficient mice display POP, thinner vaginal wall, and lower urinary tract dysfunction through an inability of urogenital tissues to replenish elastic fibers after parturition (Liu et al, 2006). LOX and LOXL3 protein levels are significantly decreased in POP patients (Alarab et al, 2010;Zhao and Zhou, 2012). LOXL2 mRNA levels are significantly decreased in postmenopausal POP patients compared with asymptomatic postmenopausal controls (Drewes et al, 2005).…”

Section: Introductionmentioning

confidence: 96%

Estradiol plays a role in regulating the expression of lysyl oxidase family genes in mouse urogenital tissues and human Ishikawa cells

Zong

Jiang

Zhao

et al. 2015

J. Zhejiang Univ. Sci. B

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Abstract:The lysyl oxidase (LOX) family encodes the copper-dependent amine oxidases that play a key role in determining the tensile strength and structural integrity of connective tissues by catalyzing the crosslinking of elastin or collagen. Estrogen may upregulate the expression of LOX and lysyl oxidase-like 1 (LOXL1) in the vagina. The objective of this study was to determine the effect of estrogen on the expression of all LOX family genes in the urogenital tissues of accelerated ovarian aging mice and human Ishikawa cells. Mice and Ishikawa cells treated with estradiol (E2) showed increased expression of LOX family genes and transforming growth factor β1 (TGF-β1). Ishikawa cells treated with TGF-β1 also showed increased expression of LOX family genes. The Ishikawa cells were then treated with either E2 plus the TGF-β receptor (TGFBR) inhibitor SB431542 or E2 alone. The expression of LOX family genes induced by E2 was reduced in the Ishikawa cells treated with TGFBR inhibitor. Our results showed that E2 increased the expression of the LOX family genes, and suggest that this induction may be mediated by the TGF-β signal pathway. E2 may play a role in regulating the expression of LOX family genes.

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“…Three studies found reduced LOXL1 expression in pre-menopausal, post-menopausal, or a mixed population of women with POP, suggesting a mechanism of sub-optimal elastin polymerization leading to FPOP. 15,16,17 The group subsequently found increased CpG methylation in the LOXL1 gene promoter in DNA from a mixed population of women with FPOP and lower LOXL1 mRNA levels suggesting a possible epigenetic mechanism. 18 Conversely, Jung et al found increased expression of LOXL1 mRNA in post-menopausal women with FPOP, which they proposed was due to compensatory induction of LOXL1 expression secondary to aberrant cross-linking of tropoelastin.…”

Section: Introductionmentioning

confidence: 99%

Mutation Screen of LOXL1 in Patients With Female Pelvic Organ Prolapse

Neupane¹,

Sadeghi²,

Fu³

et al. 2014

Female Pelvic Medicine &Amp; Reconstructive Surgery

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Objectives The LOXL1 (lysyl oxidase-like 1) gene encodes a copper-dependent monoamine oxidase that catalyzes the deamination of a lysine residue in the crosslinking of tropoelastin monomers to form elastin. LOXL1-KO mice do not deposit normal elastic fibers in their genitourinary tract resulting in post-partum pelvic organ prolapse and lower urinary tract dysfunction with decreased bladder capacity and lower voiding pressure. We sought to identify which single nucleotide polymorphisms (SNPs) in the LOXL1 coding sequence play a role in female pelvic organ prolapse (FPOP). Methods A total of 66 patients were screened, 48 in the case group and 18 in the control group. The 7 exons of LOXL1 were evaluated for any polymorphisms. Results Three missense sequence changes (Arg141Leu, Gly153Asp, and Ser159Ala) and three silent mutations (Asp292Asp, Ala320Ala, and Ile521Ile) were identified. None of these polymorphisms were found to differ significantly in frequency in the case group compared to the control group. Conclusion Our findings do not support an association of any LOXL1 exonal SNPs with the diagnosis of FPOP.

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Decreased expression of elastin, fibulin‐5 and lysyl oxidase‐like 1 in the uterosacral ligaments of postmenopausal women with pelvic organ prolapse

Abstract: There was decreased expression of fibulin-5 and LOXL1 in the uterosacral ligaments of patients with pelvic organ prolapse, while the elastin expression was equivalent, which may suggest the possibility of defects in elastic fiber remodeling in the postpartum period and contribute to POP.

Cited by 51 publications

References 25 publications

Effect of Pregnancy and Delivery on Cytokine Expression in a Mouse Model of Pelvic Organ Prolapse

Effect of Pregnancy and Delivery on Cytokine Expression in a Mouse Model of Pelvic Organ Prolapse

Estradiol plays a role in regulating the expression of lysyl oxidase family genes in mouse urogenital tissues and human Ishikawa cells

Mutation Screen of LOXL1 in Patients With Female Pelvic Organ Prolapse

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