The uterine cervix functions as a rigid, connective tissue-rich sphincter at the distal end of the uterus. In the course of normal pregnancy, the cervix gradually becomes softer as the collagenous stroma is remodeled. Correct timing of cervical softening is important because too early cervical softening (incompetent cervix) can either directly lead to premature delivery, or indirectly hasten premature delivery by constituting a weakened sphincter in premature labor. Ultrastructural findings in all species show that cervical softening is concomitant with the dissociation and disorganization of the normally tightly woven and well- aligned collagen fibers and bundles. However, the molecular basis for cervical softening is poorly understood. Collagen-binding proteins such as the proteoglycans decorin, fibromodulin, and lumican, and glycoproteins thrombospondin-2 and type V collagen have been shown to affect collagen fibrillogenesis in vitro or collagen fibril morphology and tissue mechanical properties in vivo. The applicant's hypothesis is that the reorganization of the fibrous collagen network is the cause of cervical softening, and that this reorganization is achieved by the altered synthesis or distribution of cervical collagen-binding matrix proteins. The applicant proposes to pursue the following specific aims in a mouse model of cervical softening: 1. Determine the relationship between expression pattern of collagen-binding matrix proteins, the cervical mechanical properties, and the collagen fiber morphology in uterine cervix of normal mice, and transgenic mice deficient in decorin, fibromodulin, lumican and thrombospondin. 2. The potential functional defect in cervical softening will be tested by the induction of preterm delivery with the antiprogesterone agent Mifepristone (RU-486). The significance of these studies is that a better understanding of the molecular basis of cervical softening will allow the development of techniques for early detection of susceptibility for premature cervical softening, and the design of effective preventative measures, or treatment regimens for better patient management.
| Kokenyesi, Robert; Armstrong, Lucas C; Agah, Azin et al. (2004) Thrombospondin 2 deficiency in pregnant mice results in premature softening of the uterine cervix. Biol Reprod 70:385-90 |
