Relaxin positively regulates matrix metalloproteinase expression in human lower uterine segment fibroblasts using a tyrosine kinase signaling pathway.
Despite the importance of relaxin to normal parturition in various species and its potential as an etiological agent in preterm delivery in women, knowledge regarding the mechanisms by which relaxin alters cervical connective tissue is extremely limited. An established in vitro model for human pregnancy cervix, human lower uterine segment fibroblasts, was used to determine the effects of relaxin as well as those of progesterone on the expression of matrix metalloproteinases and tissue inhibitor of metalloproteinase-1. The results demonstrate that relaxin is a positive regulator of matrix metalloproteinase expression, as it stimulates the expression of procollagenase protein and mRNA levels, stimulates prostromelysin-1 protein and mRNA levels, and inhibits tissue inhibitor of metalloproteinase-1 protein expression. Stimulation of procollagenase and prostromelysin-1 expression by relaxin does not involve phorbol-12-myristate-13-acetate- sensitive PKCs. Relaxin-stimulated tyrosine phosphorylation of the putative receptor and inhibition by a receptor tyrosine kinase inhibitor suggest that the relaxin receptor is probably a tyrosine kinase receptor. Inhibition of c-Raf protein expression using an antisense oligonucleotide inhibits relaxin regulation of matrix metalloproteinase and tissue inhibitor of metalloproteinase-1, suggesting that a signaling pathway involving c-Raf kinase mediates relaxin action.
Palejwala
S
S
Department of Obstetrics, Gynecology, and Women's Health, New Jersey Medical School, Newark, New Jersey 07103, USA.
Stein
D E
DE
Weiss
G
G
Monia
B P
BP
Tortoriello
D
D
Goldsmith
L T
LT
D002478:Cells, Cultured; D017364:Collagenases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004792:Enzyme Precursors / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D012065:Relaxin / Q000494:pharmacology* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D014599:Uterus / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism
D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D061965:Matrix Metalloproteinase Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D014443:Tyrosine; D011374:Progesterone; D012065:Relaxin; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D019908:Proto-Oncogene Proteins c-raf; D011493:Protein Kinase C; D017364:Collagenases; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; C022440:procollagenase; C048047:prostromelysin