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When fibroblasts are cultured in contracting collagen matrices, matrix metalloproteinase-1 (MMP-1, collagenase-1) is induced. In the present study we demonstrate that p38alpha mitogen-activated protein kinase (p38alpha MAPK) plays a bi-directional role in the MMP-1 response to contracting floating collagen lattices (fl-coll). fl-coll, but not attached collagen lattices (att-coll), co-ordinately increased expression of MMP-1 and activities of p38alpha and MKK3/6 (MAPK kinase 3/6). However, treatment of primary fibroblasts cultured in fl-coll with increasing doses of SB203580, an inhibitor of p38alpha and p38beta, caused a bipolar pattern of MMP-1 expression. Partial inhibition of p38 MAPK activity resulted in the lowest level of MMP-1 expression, whereas total inhibition of p38 activity led to MMP-1 levels as high as in the absence of inhibitor. The activation/inhibition of p38alpha was apparently responsible for the observed phenomena, as supported by three lines of evidence. (1) p38alpha was the predominant isoform sensitive to SB203580 in primary fibroblasts. (2) Fibroblasts transfected with increasing dose of a dominant negative p38alpha (p38DN) similarly demonstrated the bipolar pattern of MMP-1 expression induced by fl-coll. (3) The bipolar MMP-1 expression occurred during the gradual, linear inhibition of p38alpha kinase activity by both inhibitors, SB203580 and p38DN. Nuclear factor-kappaB (NF-kappaB), a previously identified positive regulator of MMP-1 expression induced by fl-coll [Xu, Zutter, Santoro and Clark (1998) J. Cell Biol. 140, 709-719] was mediated by fl-coll-activated p38alpha. However, the fl-coll-induced expression of MMP-1 facilitated by p38alpha suppression was maintained independent of NF-kappaB activity, suggesting the existence of a p38alpha-dependent antagonistic pathway. We conclude that fl-coll-induced MMP-1 expression is the net outcome of opposing effects mediated by p38alpha. Therefore, the level of p38alpha kinase activity may provide a fine-tuned control of MMP-1 gene expression in response to biomechanical signals.

p38 mitogen-activated kinase is a bidirectional regulator of human fibroblast collagenase-1 induction by three-dimensional collagen lattices