And Collagenaseresistant rr MICE

r/r the uterus of previously pregnant homozygous (r/r) females and not the heterozygous (r/+) females.

Effects on Collagen Homeostasis

These findings illustrate aspects of the dynamic relationship in a specific tissue between collagen synthesis, on one hand, and collagen degradation on the other. We have noted, in unpublished observations, using riboprobes for the mouse interstitial collagenase and in situ hybridization, that there is expression of the collagenase mRNA of a spotty nature in clusters of basal keratinocytes in the skin (also see chapter 12). Some cells in the dermis, presumably fibroblasts, also show the presence of collagenase mRNA. Collagenase-1 (MMP-1) is also expressed in human keratinocytes in inflammation and wounding.43-45 Data from several laboratories indicate that epithelial cells such as keratinocytes as well as various mesenchymal cells bind to type I collagen matrices using a2p1 integrins on the cell surfaces46,47(see chapter 8). In wounded epidermis, migrating keratinocytes continue to express these collagen-binding a2p1 integrins but then redistribute them such that they are concentrated on the frontobasal portions of the cell.47 Ligation via this integration is associated with induction of expression of collagenase, in human keratinocytes, MMP-1;46,47 antibodies to the a2p1 integrin blocks the collagenase induction. Interestingly, the human keratinocytes require active collagenase for migration and although collagen from the r/r mice can induce collagenase gene expression, the collagen is not cleaved and the cells do not migrate.47 In other systems, e.g. utilizing melanoma cells, binding to type I collagen also induces collagenase gene expression; cleavage of the collagen then "reveals" sites for binding by the avp3 integrin, ligation of which results in sustained viability of the cells through inhibition of programmed cell death (apoptosis).48

We thus envision a sequence of focal remodeling events in the dermis in which keratinocytes and fibroblasts are repeatedly stimulated through injury such as UV irradiation or mechanical trauma to release various cytokines that stimulate matrix degradation and synthesis; these responses also involve cell contacts with extracellular matrix components (Fig. 10.6). Normally, the extra collagen accumulated is eventually degraded through the action of collagenases and the remodeling cycle subsides. In the case of the r/r mice, the proteolytic degradation of the deposited collagen cannot take place because of the targeted mutations around the cleavage site and thus collagen accumulates. Failure to degrade the type I collagen results in retention of some of the other excellular matrix components intimately associated with type I collagen. The remodeling sequences suggested for the skin are based not only on our observations in the r/r mice but also on concepts utilized for years as a framework to consider remodeling events in bone.

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