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 prepared from rat skin and acetylated with either [3H]- or [14C] acetic anhydride. The radiolabelled collagen was added to sterile cotton buds and incubated at 37 degrees C to allow the collagen to form native fibrils that were firmly adsorbed to the cotton matrix. After subcutaneous implantation of the collagen-gelled cotton buds into rats, the radiolabelled collagen was progressively removed over a period of weeks by an infiltrating granuloma. Of the agents that were administered directly into the cotton buds using subcutaneously implanted osmotic mini-pumps, only the synthetic collagenase inhibitors CI-A (containing a hydroxamate moiety as a zinc ligand) and CI-C (containing a thiol moiety as a zinc ligand) were able to prevent the removal of collagen: their efficacy correlated with the level of collagenase inhibitory activity assayed in the exudate fluid sequestered within the cotton bud granuloma. Of the agents that were administered systemically, including anti-inflammatory drugs and other compounds used as therapies for arthritis, only hydrocortisone was able to inhibit the removal of radiolabelled collagen. These results suggest that, in this model, interstitial collagenase, a member of the matrix metalloproteinase family, comprised the major degradative pathway for collagen. The collagen-gelled cotton bud model is a useful test system for delineating those processes that result in collagen catabolism. In addition, the model can be used for testing agents, including those of limited or unknown systemic bioavailability, in order to discover novel therapeutic agents for preventing collagen degradation in connective tissue diseases such as arthritis.
Karran
E H
EH
SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK.
Dodgson
K
K
Harris
S J
SJ
Markwell
R E
RE
Harper
G P
GP
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001682:Biological Availability; D003094:Collagen / Q000378:metabolism*; D004343:Drug Implants; D016166:Free Radical Scavengers; D005782:Gels; D003368:Gossypium; D006099:Granuloma / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008247:Lysosomes / Q000187:drug effects; D061965:Matrix Metalloproteinase Inhibitors; D008744:Methylamines / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D000893:Anti-Inflammatory Agents; D004343:Drug Implants; D016166:Free Radical Scavengers; D005782:Gels; D061965:Matrix Metalloproteinase Inhibitors; D008744:Methylamines; D011480:Protease Inhibitors; D003094:Collagen; C027451:methylamine