src‐related tyrosine kinases regulate transcriptional activation of the interstitial collagenase gene, MMP‐1, in interleukin‐1‐stimulated synovial fibroblasts

Abstract

Objective. To characterize tyrosine kinases that contribute to the transcription of interstitial collagenase.Methods. Four thousand six hundred fourteen basepairs of the rabbit collagenase promoter region were cloned and sequenced. Plasmids containing collagenase promoter fragments linked to the luciferase reporter gene were transiently transfected into primary rabbit synovial fibroblasts. Regulation of gene activation by inflammatory mediators and tyrosine kinase inhibitors was assessed. To identify specific tyrosine kinases that contribute to collagenase gene expression, v-src was transiently expressed in rabbit synovial fibroblasts along with collagenase promoter construct$, and basal and interleukin-1 (IL-lbinduced collagenase transcription was assayed.Results. An inhibitor of src-related tyrosine kinases, herbimycin A, inhibited increases of collagenase messenger RNA in IL-1-and phorbol myristate acetatetreated fibroblasts. Transcriptional activation of collagenase by IL-1 was also inhibited by herbimycin A. Expression of v-src in synovial fibroblasts enhanced basal and IL-l-inducible transcription.Conclusion. Activation of collagenase transcription by inflammatory mediators involves activation of an src-related tyrosine kinase.The matrix metalloproteinases, a family of zincand calcium-dependent enzymes, play a central role in Supported by grants from the NIH (AR-26599) and the RGK Foundation, a NSRA Postdoctoral Fellowship (F32-AR-08216

Distinct pathways in the over-expression of matrix metalloproteinases in human fibroblasts by relaxation of mechanical tension

“…Xu and Clark (1997) have indeed shown that PKC-ζ is activated in RCG and participates in the up-regulation of the MMP-1. Other authors (Sudbeck et al, 1994;Vincenti et al, 1996) and ourselves (Lambert et al, 1998) have also demonstrated that TPA-induced expression of MMP-1 is inhibited by tyrosine kinase inhibitors, suggesting that PKC may act upstream of Src in the upregulation of the MMPs by phorbol esters and CD, and possibly also in RCG.…”

“…In this context, it is worth noting that the transient expression of v-src induces MMP-1 expression in rabbit synovial fibroblasts (Vincenti et al, 1996). Furthermore, the genetic suppression of src in mice decreases bone degradation resulting in an osteopetrotic phenotype (Soriano et al, 1991).…”

Lipid Lowering by Diet Reduces Matrix Metalloproteinase Activity and Increases Collagen Content of Rabbit Atheroma

“…In the case of MMP-1, constituents of oxidatively modified lipoproteins that stimulate protein kinase C might link to the activator protein-1 (AP1)-mediated transcriptional regulation that plays a key role in controlling transcription of MMP-1. 31 Gelatinase-B, also known as 92-kD gelatinase, or MMP-9, may contribute importantly to instability of human atherosclerotic plaques. 8,32 The regulation of tran- …”

Macrophage Migration Inhibitory Factor Up-regulates Expression of Matrix Metalloproteinases in Synovial Fibroblasts of Rheumatoid Arthritis

“…On the other hand, tyrosine kinase is another important mediator for the regulation of MMP-1 transcription (53)(54)(55). Tyrosine kinase can be classified into the receptor type and nonreceptor type; however, it is not clear which type of tyrosine kinase is involved in the signal transduction for the up-regulation of MMPs by MIF.…”

“…Tyrosine kinase can be classified into the receptor type and nonreceptor type; however, it is not clear which type of tyrosine kinase is involved in the signal transduction for the up-regulation of MMPs by MIF. It was reported that transcriptional activation of MMP-1 by TPA and IL-1␤ was inhibited by herbimycin A, but not by tyrphostin A25, an epidermal growth factor receptor tyrosine kinase inhibitor (53). Herbimycin A exerts a selective inhibitory effect on src-related tyrosine kinase (56).…”