Transforming growth factor-beta induces collagenase-3 expression by human gingival fibroblasts via p38 mitogen-activated protein kinase

Human collagenase-3 (matrix metalloproteinase 13 (MMP-13)) is characterized by exceptionally wide substrate specificity and restricted tissue specific expression. Human skin fibroblasts in culture express MMP-13 only when the y are in three-dimensional collagen (Ravanti, L., Heino, J., Lopez-Otin, C, , and Kahari. V.-M. (1999) J. Biol. Chem. 274, 2446-2455). Here we show tha t MMP-13 is expressed by fibroblasts during normal human gingival wound rep air. Expression of MMP-13 by human gingival fibroblasts cultured in monolay er or in collagen gel was induced by transforming growth factor-beta 1 (TGF -beta 1). Treatment of gingival fibroblasts with TGF-beta 1 activated two d istinct mitogen-activated protein kinases (MAPKs): extracellular signal-reg ulated kinase 1/2 (ERK1/2) in 15 min and p38 MAPK in 1 and 2 h. Induction o f MMP-13 expression by TGF-beta 1 was blocked by SB203580, a specific inhib itor of p38 MAPK, but not by PD98059, a selective inhibitor of ERK1/2 activ ation. Adenovirus-mediated expression of dominant negative p38 alpha and c- Jun potently inhibited induction of MMP-13 expression in gingival fibroblas ts by TGF-beta 1. Infection of gingival fibroblasts with adenovirus for con stitutively active MEK1 resulted in activation of ERK1/2 and JNK1 and up-re gulation of collagenase-1 (MMP-1) and stromelysin-1 (MMP-3) production but did not induce MMP-13 expression. In addition, activation of p38 MAPK by co nstitutively active MKK6b or MKK3b was not sufficient to induce MMP-13 expr ession. These results show that TGF-beta-elicited induction of MMP-13 expre ssion by gingival fibroblasts is dependent on the activity of p38 MAPK and the presence of functional AP-1 dimers. These observations demonstrate a fu ndamental difference in the regulation of collagenolytic capacity between g ingival and dermal fibroblasts and suggest a role for MMP-13 in rapid turno ver of collagenous matrix during repair of gingival wounds, which heal with minimal scarring.