View Full Version : Sadowski & Steinmeyer (2001). Effects of tetracyclines on the production of matrix metalloproteinases and plasminogen activators as well as of their natural inhibitors, tissue inhibitor of metalloproteinases-1 and plasminogen activator inhibitor
01-01-2002, 08:30 AM
• Sadowski T and Steinmeyer J (2001). Effects of tetracyclines on the production of matrix metalloproteinases and plasminogen activators as well as of their natural inhibitors, tissue inhibitor of metalloproteinases-1 and plasminogen activator inhibitor-1. Inflamm Res. 50 (3): 175-82. Summary: OBJECTIVE: Evaluation of tetracycline effects on the expression of MMP-1, MMP-3, tissue inhibitor(s) of metalloproteinase-1 (TIMP-1), plasminogen activators (PA), and PA inhibitor-1, which are all involved in the ultimate regulation of MMP activity could provide new insight into how tetracyclines achieve their cartilage preserving effects. MATERIALS AND METHODS: We used bovine articular chondrocytes cultured in alginate gel beads for our studies which were initially treated with 10 microM tetracyclines in the presence of IL-1. Only significant effects were studied at additional concentrations. Expression of mRNA was analyzed by RT-PCR-ELISA. The activity of enzymes and TIMP was measured by functional assays; whereas, the level of PAI-1 was determined by ELISA. RESULTS: Treating chondrocytes with IL-1 induced the expression of MMPs and downregulated TIMP-1 but stimulated both the expression of PAs and PAI-1. When tested at 10 microM only minocycline reduced collagenase activity and expression of MMP-1. Further pharmacokinetic analysis revealed IC50 values of 26 microM and 16 microM for the inhibition of collagenase activity and mRNA expression, respectively. Production of MMP-3 was only decreased by tetracycline (IC50 = 45.4 microM). No effects of tetracyclines could be observed on proteoglycan degradation, TIMP activity and the production of PAs, PAI-1, and TIMP-1. CONCLUSIONS: We conclude that the inhibition of MMPs by tetracyclines occurs mainly via down-regulation of the respective gene expression. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11339506> Institute of Pharmacology and Toxicology, University of Bonn, Germany. email@example.com
01-02-2002, 05:36 PM
Dr. Young, excuse my ignorance but this is all pretty Greek to me. Can you dummy this down for me? I don't even see minocycline mentioned by name but I assume it is part of the tetracycline family. If it is, what other drugs could possibly show the same results?
01-03-2002, 11:51 AM
Sorry, I tried to do that in the front headliner for the article which you can see if you open to the topic list.
These authors did their tests on chondrocytes (the cells that make cartilage in your disc and joints). They stimulated these cells with IL-1 (interleukin-1, a proinflammatory cytokine) to produce metalloproteinases (these are enzymes that break down extracellular matrix proteins). I suppose that is occurs when there is inflammation and that is why the joint surfaces break down, due to the release of these enzymes. There are several types of metalloproteinases, called MMP-1, MMP-2. The authors also looked at collagenase (the enzyme that breaks down collagen, a major component of scar and joint cartilage) and also plasminogen activator (which plays a role in breaking down clots).
When they treated the IL-1 activated chondrocytes with minocycline, they found reduced expression and activity of MMP-1, MMP-3, collagenase, and plasminogen activator. The concentrations that produced about half of the effect (IC50) were respectively 26 micromolar and 16 micromolar for suppressing the enzyme activity and for suppressing gene expression. In other words, minocycline apparently turns off the gene that produces these enzymes. They need a high concentrations of minocycline to shut off the enzyme altogether (presumably just a little bit of gene expression can still produce some enzyme).
Who would have thunk that an antibiotic would turn off genes? Tetracyline itself apparently turns off some genes but only for MMP-3. So, the ability to turn off multiple genes is something that minocycline has and which ordinary tetracycline does not.
One lives and learns. I would not be at all surprised if many drugs have all sorts of effects on other genes. For example, I was recently speaking to a woman who is taking Dantrium for spasticity. She was asking me whether she was getting hairier because she received methylprednisolone. Being very familiar to methylprednisolone side-effects, I told her that I did not think so. But, something jogged my mind. I went to look and indeed one reported side-effect of dantrium in increased body hairs, hirsutism. So, dantrium seems to do all sorts of stuff to cells that we don't know. That also reminded me that Martin Schwab reported several years ago in conversation, but did not publish, that dantrium blocks the Nogo receptor. To my knowledge, nobody has ever followed up on that finding.