Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The extra domain-A (EDA), present in fibronectin (FN) molecules arising from alternatively spliced transcripts, appears only during specific biological and pathogenic processes. However, its function is poorly understood. To define the physiologic role of this domain in joint connective tissue, the biological effects on rabbit cartilage explants, chondrocytes, and synovial cells were studied. A recombinant EDA protein (rEDA) increased proteoglycan release (3. 6-fold) in cartilage explant cultures and markedly induced production of matrix metalloproteinase (MMP)-1 in chondrocytes. In addition, rEDA induced MMP-1, MMP-3, and MMP-9 in synovial cells. These effects were elicited only by rEDA, while its neighboring type III repeats, III(11) or III(12), scarcely had any such effects. Interestingly, reorganization of F-actin stress fibers accompanied MMP-1 expression in synovial cells treated with rEDA, suggesting alteration of cellular phenotype. Subsequent Northern blotting revealed expression of pro-inflammatory cytokines, including interleukin (IL)-1alpha and IL-1beta, was induced by rEDA prior to MMP-1 expression. Delayed MMP-1 expression suggests that rEDA-induced IL-1s promote MMP-1 expression in an autocrine manner. This hypothesis is supported by the reduction of EDA-induced MMP-1 production by IL-1 receptor antagonist. The effect of EDA on MMP-1 production was reduced by connection with an adjacent type III repeat on either the NH(2) or COOH side of EDA and was abolished by connection on both sides of EDA, suggesting that exposure of either the NH(2) or COOH terminus of EDA domain by proteolytic cleavage releases the inducing activity. In agreement with these results, full-length cellular FN did not induce MMP-1 production. Furthermore, a 160-kDa EDA-positive FN fragment, which was purified from human placental tissue and corresponds to the region from NH(2) terminus through the EDA, induced MMP-1 production. Taken together, these results suggest that the EDA in FN fragments triggers alterations of cell physiology and plays a role in matrix degradation in joint connective tissue.
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PMID:The fibronectin extra domain A activates matrix metalloproteinase gene expression by an interleukin-1-dependent mechanism. 1052 65

Tenascin-C is an extracellular matrix glycoprotein whose monomers include eight consecutive fibronectin type III-like repeats, encoded by exons 10-16, and which are subject to alternative splicing. Transcripts containing these exons are expressed during tissue wounding and active tissue remodelling. Human fetal membranes have been proposed to undergo active tissue remodelling as part of the mechanisms leading to their rupture and immunoreactive tenascin-C has been detected in this tissue. Employing reverse transcription-polymerase chain reaction (RT-PCR) and exon-specific primers, products corresponding to multiple splicing events in the alternatively spliced region have now been identified. The overall splicing pattern would indicate that the major transcripts correspond to complete exclusion of the alternatively spliced region; inclusion of only exon 16; and inclusion of exons 10-14 and 16, including or excluding exon 12. The sole site in tenascin-C susceptible to cleavage by matrix metalloproteinases (MMP)-2 and MMP-3 is found within the exon 12 encoded repeat, therefore translation of isoforms which include or exclude exon 12 may produce 'large' tenascins mediating functions ascribed to this form but susceptible or resistant to these MMPs. The demonstration of expression of 'large' tenascin mRNA isoforms supports the concept that fetal membranes at term are a site of active tissue remodelling.
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PMID:Alternatively spliced tenascin-C mRNA isoforms in human fetal membranes. 1054 70