A SIMPLE IN-VIVO MODEL OF COLLAGEN DEGRADATION USING COLLAGEN-GELLED COTTON BUDS - THE EFFECTS OF COLLAGENASE INHIBITORS AND OTHER AGENTS

A simple in vivo model of collagen degradation has been developed, and the effects of various agents have been tested. Type I collagen was p repared from rat skin and acetylated with either [H-3]- or [C-14] acet ic anhydride. The radiolabelled collagen was added to sterile cotton b uds and incubated at 37 degrees C to allow the collagen to form native fibrils that were firmly adsorbed to the cotton matrix. After subcuta neous implantation of the collagen-gelled cotton buds into rats, the r adiolabelled collagen was progressively removed over a period of weeks by an infiltrating granuloma. Of the agents that were administered di rectly into the cotton buds using subcutaneously implanted osmotic min i-pumps, only the synthetic collagenase inhibitors CI-A (containing a hydroxamate moiety as a zinc ligand) and CI-C (containing a thiol moie ty as a zinc ligand) were able to prevent the removal of collagen: the ir efficacy correlated with the level of collagenase inhibitory activi ty assayed in the exudate fluid sequestered within the cotton bud gran uloma. Of the agents that were administered systemically, including an ti-inflammatory drugs and other compounds used as therapies for arthri tis, only hydrocortisone was able to inhibit the removal of radiolabel led collagen. These results suggest that, in this model, interstitial collagenase, a member of the matrix metalloproteinase family, comprise d the major degradative pathway for collagen. The collagen-gelled cott on bud model is a useful test system for delineating those processes t hat result in collagen catabolism. In addition, the model can be used for testing agents, including those of limited or unknown systemic bio availability, in order to discover novel therapeutic agents for preven ting collagen degradation in connective tissue diseases such as arthri tis.