P. Zigrino et al., Collagen-induced proMMP-2 activation by MT1-MMP in human dermal fibroblasts and the possible role of alpha 2 beta 1 integrins, EUR J CELL, 80(1), 2001, pp. 68-77
Culture of human dermal fibroblasts within a three-dimensional matrix compo
sed of native type I collagen fibrils is widely used to study the cellular
responses to the extracellular matrix. Upon contact with native type I coll
agen fibrils human skin fibroblasts activate latent 72-kDa type IV collagen
ase/gelatinase (MMP-2) to its active 59- and 62-kDa forms. This activation
did not occur when cells were cultured on plastic dishes coated with monome
ric type I collagen or its denatured form, gelatin. Activation could be inh
ibited by antibodies against MT1-MMP, by the addition of TIMP-2 and by prev
ention of MT1-MMP processing. MT1-MMP protein was detected at low levels as
active protein in fibroblasts cultured as monolayers. In collagen gel cult
ures, an increase of the active, 60-kDa MT1-MMP and an additional 63-kDa pr
otein corresponding to inactive MT1-MMP was detected. Incubation of medium
containing latent MMP-2 with cell membranes isolated from fibroblasts grown
in collagen gels caused activation of the enzyme. Furthermore, regulation
of MT1-MMP expression in collagen cultures seems to be mediated by alpha2 b
eta1 integrins. These studies suggest that activation of the proMMP-2 is re
gulated at the cell surface by a mechanism which is sensitive to cell cultu
re in contact with physiologically relevant matrices and which depends on t
he ratio of proenzyme and the specific inhibitor TIMP-2.