HOXA11 is critical for development and maintenance of uterosacral ligaments and deficient in pelvic prolapse
Kathleen A. Connell, … , Richard Bercik, Hugh S. Taylor
Kathleen A. Connell, … , Richard Bercik, Hugh S. Taylor
Published February 14, 2008
Citation Information: J Clin Invest. 2008;118(3):1050-1055. https://doi.org/10.1172/JCI34193.
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Research Article Reproductive biology

HOXA11 is critical for development and maintenance of uterosacral ligaments and deficient in pelvic prolapse

Abstract

Pelvic organ prolapse (POP) is a common, debilitating disorder affecting millions of women. Uterosacral ligaments (USLs) are the main supportive structures of the uterus and vagina and are often attenuated in women with POP. Although the mechanical strength of USLs is known to be dependent on collagen synthesis and catabolism and the degradation protein MMP2 has been implicated in POP, the molecular mechanisms involved in the development of POP are currently unknown. Homeobox (HOX) genes are transcriptional regulators that orchestrate embryonic development of the urogenital tract. We demonstrated here that HOXA11 was essential for organogenesis of the USL by showing that USLs were absent in Hoxa11-null mice. We compared expression of HOXA11, collagen type I, collagen type III, MMP2, and MMP9 in USLs of women with and without POP. Expression of HOXA11 and both collagens was dramatically decreased while MMP2 was increased in women with POP. Constitutive expression of Hoxa11 in murine fibroblasts resulted in significantly increased expression of collagen type III and decreased expression of MMP2. These results identified HOXA11 as an essential gene for the development of the USL and suggested that women with POP might have weakened connective tissue due to changes in a signaling pathway involving HOXA11, collagen type III, and MMP2.

Authors

Kathleen A. Connell, Marsha K. Guess, Heidi Chen, Vaagn Andikyan, Richard Bercik, Hugh S. Taylor

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Figure 1

Evaluation of HOXA11 expression in human and murine USLs.

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Evaluation of HOXA11 expression in human and murine USLs. ...
(A) Intranuclear expression of HOXA11demonstrated in human USLs. (B) PCR products confirming HOXA11 expression in human USLs. NEG, negative control; POP, RT-PCR using RNA obtained from a subject with POP; CTL, RT-PCR using material from a control subject; POS, positive control. (C) Comparison of pelvic anatomy between Hoxa11-null and wild-type mice. Note the absence of the USLs and increased mobility of the uterus, allowing visualization of the posterior vagina, in the Hoxa11-null mouse compared with the definitive USLs in the wild-type mouse, which stabilizes the uterus and vagina. Arrows indicate USLs arising from the cervix. Sig, sigmoid colon. (D) RT-PCR results showing expression of Hoxa11 in the USLs of wild-type and Hoxa11 heterozygous mice. Paracervical tissue was used for RT-PCR in Hoxa11-null mice.