HOXA11 Promotes Fibroblast Proliferation and Regulates p53 in Uterosacral Ligaments

Connell, Kathleen A.; Guess, Marsha K.; Chen, Heidi W.; Lynch, Tara A.; Bercik, Richard; Taylor, Hugh S.

doi:10.1177/1933719109334260

Cited by 25 publications

(24 citation statements)

References 33 publications

(64 reference statements)

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“…Decreased synthesis of these fibrils would expectedly reduce the total COLI and COLIII content in the USLs and uterus. Alternatively, decreased collagen production in both USLs and uteri may be a result of decreased proliferation of fibroblasts, as our previous observations showed that Hoxa11 overexpression promoted cell proliferation in murine fibroblasts and in human primary USL cell cultures through a p53-dependent pathway [36].…”

Section: Discussionmentioning

confidence: 92%

Knockdown of Hoxa11 In Vivo in the Uterosacral Ligament and Uterus of Mice Results in Altered Collagen and Matrix Metalloproteinase Activity1

Guess

Datar

et al. 2012

Biology of Reproduction

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Homeobox (HOX) genes are evolutionarily conserved genes encoding transcription factors that regulate mammalian embryonic growth and development of the urogenital tract. In both humans and mice, HOXA11 persists in the adult reproductive tract and is thought to play an important role in maintaining tissue developmental plasticity by regulating the expression of genes involved in extracellular matrix metabolism in the reproductive organs. Previously, we have shown that HOXA11 is necessary for development of the uterosacral ligaments in mice and is deficient in women with pelvic organ prolapse. Therefore, we hypothesized that Hoxa11 regulates the synthesis and/or metabolism of collagens in the uterosacral ligaments and uterus, and tested this by establishing an in utero and peritoneal Hoxa11 gene knockdown system in C57/BL6 mice using vectors bearing Hoxa11 short hairpin RNA. Specific knockdown of Hoxa11 transcripts and protein levels were confirmed versus control vectors. Protein and mRNA expression of collagen types I and III exhibited significant decreases following Hoxa11 knockdown according to Western blot analysis and real-time PCR. Tissue inhibitor of matrix metalloproteinase 1 (MMP1) expression also exhibited a significant decrease. Gelatinase zymography confirmed increases in pro-MMP2 and MMP9, as well as activated MMP2, following Hoxa11 knockdown. These results reveal that Hoxa11 knockdown in the uterosacral ligaments and uterus increases extracellular matrix degradation. More importantly, it suggests a mechanism in the weakening of the pelvic floor support in women, because decreased HOXA11 gene expression has been reported to be associated with decreased collagen and increased MMP2 expression in the uterosacral ligaments of women with pelvic organ prolapse.

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Section: Discussionmentioning

confidence: 92%

Knockdown of Hoxa11 In Vivo in the Uterosacral Ligament and Uterus of Mice Results in Altered Collagen and Matrix Metalloproteinase Activity1

Guess

Datar

et al. 2012

Biology of Reproduction

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“…Furthermore, cultured smooth muscle cells from patients with and without POP would help us to determine if there is a difference in the rate of proliferation and responsiveness to estrogen. Also there are other factors not controlled for in this trial that may have an influence on cell proliferation rates (Connell et al, 2009). Finally, a 3-D culture coculture model may better represent the complex in vivo pelvic floor supportive structures than a monolayer of smooth muscle cells.…”

Section: Discussionmentioning

confidence: 99%

The effects of estrogen, progesterone and polypropylene mesh on vaginal smooth muscle cell proliferation

Takács

Zhang

Jaramillo

et al. 2010

J. Smooth Muscle Res.

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“…Using USL tissue from prolapsed and nonprolapsed women undergoing hysterectomy they found that women with POP have decreased Hoxa11 mRNA expression compared with controls. Hoxa11 also increases proliferation of fibroblasts and human USL cells in vitro and may do so via repression of p53, a known cell-cycle suppressor [50]. Knockdown of Hoxa11 decreases collagen and increases MMP expression in mice mimicking, at least in part, the enzymatic derangements seen in women with POP [51–53].…”

Section: Animal Models Of Popmentioning

confidence: 99%

Animal models of female pelvic organ prolapse: lessons learned

Couri

Borazjani

Paraíso

et al. 2012

Expert Review of Obstetrics & Gynecology

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Pelvic organ prolapse is a vaginal protrusion of female pelvic organs. It has high prevalence worldwide and represents a great burden to the economy. The pathophysiology of pelvic organ prolapse is multifactorial and includes genetic predisposition, aberrant connective tissue, obesity, advancing age, vaginal delivery and other risk factors. Owing to the long course prior to patients becoming symptomatic and ethical questions surrounding human studies, animal models are necessary and useful. These models can mimic different human characteristics -histological, anatomical or hormonal, but none present all of the characteristics at the same time. Major animal models include knockout mice, rats, sheep, rabbits and nonhuman primates. In this article we discuss different animal models and their utility for investigating the natural progression of pelvic organ prolapse pathophysiology and novel treatment approaches. Keywordsaberrant connective tissue; animal model; female; mesh repair; pelvic organ prolapse; POP; vaginal delivery Pelvic organ prolapse (POP) consists of descent of the anterior, posterior or apical vaginal compartments. While not life-threatening, POP often results in a significant reduction in quality of life, including shame, embarrassment and sexual dysfunction. POP is also a significant economic burden to millions of women and the healthcare system since it is one of the major indications for benign gynecological surgery, accounting for over 225,000 inpatient procedures and costing more than US$1 billion per year in the USA alone [1].The pathophysiology of POP is still not well understood, but is known to involve genetic predisposition, aberrant connective tissue (CT) metabolism, pregnancy and hormonal effects, vaginal delivery, and other risk factors such as previous hysterectomy, obesity, advancing age and constipation [1]. POP often develops decades after the greatest risk © 2012 Expert Reviews Ltd * Author for correspondence: Tel.: + 1 216 444 1103, Fax: + 1 216 444 9198, damasem@ccf.org. Financial & competing interests disclosureThe authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. NIH Public Access Author ManuscriptExpert Rev Obstet Gynecol. Author manuscript; available in PMC 2013 March 01. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript factor, vaginal delivery, suggesting an additional impact of aging. Given the long time course and the complex and multifaceted nature of this disorder, animal models are a potentially useful way to improve our understanding of POP.Animal models are particularly appropriate for studying the natural progression of pathologies and investigating novel treatment approaches. However, the development of applicable animal models for POP is challenging since humans, as t...

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HOXA11 Promotes Fibroblast Proliferation and Regulates p53 in Uterosacral Ligaments

Cited by 25 publications

References 33 publications

Knockdown of Hoxa11 In Vivo in the Uterosacral Ligament and Uterus of Mice Results in Altered Collagen and Matrix Metalloproteinase Activity1

Knockdown of Hoxa11 In Vivo in the Uterosacral Ligament and Uterus of Mice Results in Altered Collagen and Matrix Metalloproteinase Activity1

The effects of estrogen, progesterone and polypropylene mesh on vaginal smooth muscle cell proliferation

Animal models of female pelvic organ prolapse: lessons learned

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