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)

Chondrocyte-derived metalloproteases have been postulated to play a role in the degradation of articular cartilage during the development of chronic arthritic disorders. TNF alpha (tumor necrosis factor alpha), an inflammatory mediator released by activated macrophages, has been detected in the synovial fluid of patients with rheumatoid diseases. We have found that TNF alpha is a potent stimulator of collagenase and stromelysin mRNA accumulation, collagenase activity, and immunoprecipitable stromelysin in monolayer cultures of adult porcine articular chondrocytes. In contrast EGF (epidermal growth factor), which stimulates collagenase and/or stromelysin synthesis in fibroblast systems, stimulated minimal amounts of these enzymes at both the message and protein levels. Nuclear run-on transcription analysis demonstrated that the TNF alpha-stimulated increase in stromelysin and collagenase message levels was, at least partially, due to increased transcription. Elevated transcription of these genes, in response to TNF alpha, was apparent by at least 2 hours post-stimulation. The degree of c-fos and c-jun stimulation by TNF alpha or EGF did not correlate with the levels of collagenase and stromelysin message stimulated by these factors. EGF stimulated significant accumulation of both c-fos and c-jun mRNAs while only very low amounts of these messages were stimulated by TNF alpha. Our data suggests that TNF alpha may contribute to articular cartilage degradation by stimulating chondrocyte-derived matrix metalloproteases. In addition the regulation of metalloprotease genes in chondrocytes may be different from their regulation in fibroblasts.
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PMID:Tumor necrosis factor alpha and epidermal growth factor regulation of collagenase and stromelysin in adult porcine articular chondrocytes. 165 9

Cells of the monocyte/macrophage lineage are involved in the development of inflammatory joint diseases such as rheumatoid arthritis. This disease is characterized by cartilage degradation and synovial membrane inflammation with a progressive loss of joint function. The pathological processes are still not well understood. Therefore it would be interesting to develop a suitable experimental in vitro model system for defined studies of monocyte/macrophage and chondrocyte interactions at the molecular level. For that purpose we cocultured chondrocytes from adult human articular cartilage with human monocytes and macrophages for defined periods of time in agarose without addition of serum. We performed zymographic and western blot analysis of culture medium, completed by quantitative RT-PCR of each chondrocyte, monocyte and macrophage RNA, respectively. The reliability of the newly established coculture systems is confirmed by causing a clear decrease of intact aggrecan in the coculture medium plus concurrent appearance of additional smaller fragments and a reduction of chondrocyte aggrecan and collagen II gene expression in the presence of monocytes. In culture medium from cocultures we detected active forms of the matrix metalloproteinases MMP-1, MMP-3 and MMP-9 accompanied by induction of gene expression of MMP-1, membrane type 1 MMP (MT1-MMP) and tissue inhibitor of metalloproteinase 2 (TIMP-2) in chondrocytes. No gene expression of MMP-9 was detectable in chondrocytes, the enzyme was solely expressed in monocytes and macrophages and was downregulated in the presence of chondrocytes. Our results suggest that MMP-9 protein in coculture medium originated from monocytes and macrophages but activation required chondrocyte-derived factors. Because addition of plasmin, a partial activator of pro-MMP-3 and pro-MMP-1, enhanced the activation of pro-MMP-9 and pro-MMP-1 in cocultures but not in monocultured macrophages, and the presence of MMP-3 inhibitor II prevented pro-MMP-9 activation, we assumed a stepwise activation process of pro-MMP-9 that is dependent on the presence of at least MMP-3 and possibly also MMP-1.
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PMID:Paracrine interactions of chondrocytes and macrophages in cartilage degradation: articular chondrocytes provide factors that activate macrophage-derived pro-gelatinase B (pro-MMP-9). 1171 48