HOXA11 is critical for development and maintenance of uterosacral ligaments and deficient in pelvic prolapse
HOXA11 is critical for development and maintenance of uterosacral ligaments and deficient in pelvic prolapse
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DOI：
10.1172/jci34193
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发表时间：
2008-03-01
影响因子：
15.9
通讯作者：
Taylor, Hugh S.
中科院分区：
文献类型：
--
作者：
Connell, Kathleen A.;Guess, Marsha K.;Taylor, Hugh S.
盆腔器官脱垂（POP）是一种常见的使人衰弱的疾病，影响着数百万妇女。子宫骶韧带（USLs）是子宫和阴道的主要支撑结构，在POP患者中通常减弱。虽然已知USLs的机械强度依赖于胶原合成和分解代谢，降解蛋白MMP2与POP有关，但目前尚不清楚POP发生的分子机制。同源盒（HOX）基因是调控胚胎泌尿生殖道发育的转录调控因子。我们通过在HOXA11缺失的小鼠中USL缺失，证明了HOXA11对USL的器官发生是必不可少的。我们比较了HOXA11、I型胶原、III型胶原、MMP2和MMP9在有和没有POP的女性USLs中的表达。在POP女性中，HOXA11和两种胶原蛋白的表达均显著降低，而MMP2的表达则显著升高。Hoxa11在小鼠成纤维细胞中的组成性表达导致III型胶原的表达显著增加，MMP2的表达显著降低。这些结果确定HOXA11是USL发展的重要基因，并提示POP女性可能由于涉及HOXA11、III型胶原和MMP2的信号通路的变化而削弱了结缔组织。
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.