Collagenases and Collagen Degradation.

Degradation of interstitial collagens probably takes place through different enzymatic mechanisms than degradation of basement membrane and pericellular collagens. Interstitial collagens are resorbed under pathological and physiological conditions by collagenases which function extracellularly and cleave polypeptide chains in the collagen triple helix at specific loci resulting in solubilization from the fibril. Production of collagenase in humans is ascribable to fibroblast-like cells which can be stimulated to synthesize new enzyme for release outside of the cell. In several inflammatory conditions, such as rheumatoid synovitis, modulation of collagenase production is mediated by interactions with surrounding inflammatory cells. Monocyte-macrophages produce a stimulatory factor, which has homologies with interleukin 1, which not only increases collagenase synthesis but also PGE2 synthesis. The PGE2 in turn has profound effects on cellular function. Production of the mononuclear cell factor is modulated by several interactions including T lymphocytes and T lymphocyte products, collagen of the extracellular matrix and the Fc portion of immunoglobulins. It is probable, from analogies with other stimulants such as phorbol myristate acetate, that the increase in collagen synthesis is controlled at the level of transcription. Further regulation of collagenase action outside of the cell is probably accomplished by proteolytic activation of a latent collagenase zymogen and interactions with inhibitory proteins also produced by cells in the local environment of the resorptive process.