Development of new therapeutic agents for preterm birth by glycosaminoglycan chain remodeling of urinary trypsin inhibitor

Abstract

This study aimed to examine the effects of the glycosaminoglycan (GAG) chain in urinary trypsin inhibitor (UTI) on uterine cervical fibroblasts (UCFs) and to apply the findings to the development of more effective therapeutic drugs for the management of preterm birth. Methods: We prepared GAG chain-remodeled UTIs by hydrolysis and /or transglycosylation by testicular hyaluronidase. These UTIs were added to UCFs obtained from gynecology operations, and the effects of UTIs on the release of IL-8, IL-6, MMP-8, and MMP-9 were examined. Results: UTIs that were not hydrolyzed tended to reduce IL-8 release more strongly than GAG chain-hydrolyzed UTIs. IL-6 was not affected by GAG chain hydrolysis of UTIs. GAG chain-hydrolyzed UTIs tended to reduce MMP-8 and MMP-9 release more strongly than non-hydrolyzed UTIs. Conclusions: Our findings suggest that the GAG chain of UTI might reduce hyaluronan during cervical ripening by reducing IL-8 release and has opposite effects on reducing MMP-8 and MMP-9 release related to collagen degradation. This insight may be helpful in the development of more effective therapeutic drugs for the management of preterm birth.

A Chondroitin Sulfate Chain of Urinary Trypsin Inhibitor Enhances Protease Inhibitory Activity of the Core Protein

“…Recently, we remodeled the GAG chain of UTI from low sulfated Ch4S to hyaluronan (HA), with no changes to the core protein to create the HA hybrid UTI (HA-UTI) as a tool for investigating native GAG chain functions as well as the possible superiority of HA-UTIs over native UTI. 13) 14) In the present study, we investigated the effect of the GAG chain on the activities of trypsin, chymotrypsin, plasmin, and pancreatic elastase. It was demonstrated that UTI having a native GAG chain showed stronger inhibitory activity on these proteases compared with HA-UTI or with UTI with only a linkage region as sugar chain moiety.…”