Regulation of the Mammalian Collagenases

Abstract

Gross and Lapiere (1962) discovered vertebrate collagenase in cultures of resorbing tadpole tissue. By ultrastructural techniques it was shown that collagenase cleaves each triple helical collagen molecule at only one site approximately three-quarters from the amino terminus (Gross and Nagai, 1965). Gross and his colleagues suggested that once the triple helical region of a collagen molecule on a fibril is cleaved, the two resulting fragments denature (at temperatures> 32°C) into non-helical gelatin polypeptides, peel off the fibril and are degraded by proteinases in the extracellular space or pinocytosed by macrophages or other cells and further degraded intracellularly. Cleavage by collagenase of the collagen triple helix still is considered the rate-limiting step in collagenolysis. Since collagenases act at neutral pH in the extracellular space, the structure and function of extracellular scaffolding would be in disarray without precise regulatory control. Early studies suggested that overabundant local production of collagenase by rheumatoid synovium (Harris et aI., 1970) or by certain invasive tumors (Hashimoto et aI., 1973; Bauer et aI., 1977) could result in loss of normal connective tissue components. Similarly, in certain normal processes such as wound healing (Grillo, 1964) and resorption of the postpartum uterus (Woessner, 1980) large amounts of collagen are resorbed over a relatively short period. Thus, in the pathologic states tissue destruction seems to be related to ineffective regulatory control. The finding that monolayer cultures of cells from many tissues produce collagenase formed the basis for model systems in which regulation of biosynthesis could be studied. With the use of such systems it became apparent that collagenolysis is regulated at multiple steps from transcription of collagenase mRNA to inhibition of active enzyme in tissues. These include: 1. Biosynthesis of procollagenase (including induction, and subsequent processing of precursor forms) 2. Packaging and secretion of procollagenase