Cell origin and paracrine control of interstitial collagenase in the guinea pig uterine cervix--evidence for a low molecular weight epithelial cell-derived collagenase stimulator.

Dilatation of the uterine cervix at parturition is achieved by degradation of type I collagen, the main structural protein in the cervix, by interstitial collagenase. In order to determine the cell origin of interstitial collagenase in the cervix, separate stromal and epithelial cell cultures were established. Using a highly sensitive and specific assay for collagenase that utilizes [3H]telopeptide-free type I collagen as a substrate, we determined that the cells of origin of collagenase were cervical stromal cells and not cervical epithelial cells. Cells of cervical epithelium produced factors in culture that stimulated stromal cell collagenase production. The addition of epithelial cells or epithelial cell-conditioned culture medium to stromal cells resulted in a dose-dependent stimulation of stromal cell collagenase production with a maximum increase of 3- or 6-fold, respectively. To characterize the collagenase-stimulatory activity produced by epithelial cells, epithelial cell-conditioned culture medium was extracted under conditions that optimized the recovery of peptides and was subjected to ion-exchange batch extraction as well as reverse-phase and size-exclusion HPLC. Collagenase-stimulatory activities were mainly recovered in neutral extracts of epithelial cell-conditioned medium with an apparent molecular mass of 6 kDa. In conclusion, interstitial collagenase is produced by cervical stromal cells and not by cervical epithelial cells. Epithelial cells, however, secrete factors of low molecular size that stimulate stromal cell collagenase production.