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Medical Forum / Diseases and Disorders / Arthritis / March 2006Matrix metalloproteinases: role in arthritis
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=16146751&query_hl=7&itool=pubmed_docsum ... ... Front Biosci. 2006 Jan 1;11:529-43. Related Articles, Links Matrix metalloproteinases: role in arthritis. Burrage PS, Mix KS, Brinckerhoff CE. Department of Biochemistry, Dartmouth Medical School, Dartmouth Hitchcock Medical Center, Lebanon, NH 03756, USA. The irreversible destruction of the cartilage, tendon, and bone that comprise synovial joints is the hallmark of both rheumatoid arthritis (RA) and osteoarthritis (OA). While cartilage is made up of proteoglycans and type II collagen, tendon and bone are composed primarily of type I collagen. RA is an autoimmune disease afflicting numerous joints throughout the body; in contrast, OA develops in a small number of joints, usually resulting from chronic overuse or injury. In both diseases, inflammatory cytokines such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) stimulate the production of matrix metalloproteinases (MMPs), enzymes that can degrade all components of the extracellular matrix. The collagenases, MMP-1 and MMP-13, have predominant roles in RA and OA because they are rate limiting in the process of collagen degradation. MMP-1 is produced primarily by the synovial cells that line the joints, and MMP-13 is a product of the chondrocytes that reside in the cartilage. In addition to collagen, MMP-13 also degrades the proteoglycan molecule, aggrecan, giving it a dual role in matrix destruction. Expression of other MMPs such as MMP-2, MMP-3 and MMP-9, is also elevated in arthritis and these enzymes degrade non-collagen matrix components of the joints. Significant effort has been expended in attempts to design effective inhibitors of MMP activity and/or synthesis with the goal of curbing connective tissues destruction within the joints. To date, however, no effective clinical inhibitors exist. Increasing our knowledge of the crystal structures of these enzymes and of the signal transduction pathways and molecular mechanisms that control MMP gene expression may provide new opportunities for the development of therapeutics to prevent the joint destruction seen in arthritis. PMID: 16146751 [PubMed - in process] It appears that MMP-13s seem to be the most destuctive and probably do the most damage in arthritis. The other MMPs probably join in on the feeding frenzy after the MMP-13s start cutting "things" into smaller pieces. jack n dalton 1: J Biol Chem. 2004 Feb 20;279(8):6286-95. Epub 2003 Dec 3. Cleavage of fibromodulin in cartilage explants involves removal of the N-terminal tyrosine sulfate-rich region by proteolysis at a site that is sensitive to matrix metalloproteinase-13. Heathfield TF, Onnerfjord P, Dahlberg L, Heinegard D. Department of Cell and Molecular Biology, Section for Connective Tissue Biology, Lund University, SE-22184 Lund, Sweden. Integrity of cartilage fails in joint disease. The current work aimed to identify candidate active proteinases in joint diseases using an in vitro model for cartilage degradation induced by interleukin-1. A critical event in the process of cartilage destruction in joint disease is the failure of the collagen fiber network to maintain integrity. Proteins binding to the surface of the fibers are likely early points of failure. Fibromodulin, a member of the leucine-rich repeat protein family, is one predominant protein in cartilage and is known for its roles in the formation of collagen fibrils and sustained interaction with these formed fibers. Cleavage removes the tyrosine sulfate-rich region in the N terminus of fibromodulin. Whereas fibromodulin bound to collagen in tissue was digested, purified fibromodulin was not cleaved. In contrast an N-terminal 10-kDa fragment, Gln19-Lys98, of the protein generated by Lys-C digestion contains the cleavage site and was a substrate cleaved by the enzyme in medium from stimulated cultures. In solution, digestion of this substrate with matrix metalloproteinase (MMP)-2, -9, -8, and -13 demonstrated that only MMP-13 was capable to efficiently cleave it. The cleavage product obtained after MMP-13 digestion was identical to that observed in cleaved fibromodulin from cartilage explant cultures stimulated with interleukin-1. MMP-13 treatment of fresh articular cartilage also produced the fragment under study. The elucidation of the enzyme responsible for such cleavage may lead to treatment modalities involving its selective inhibition for patients suffering from arthritis. The known structure of the fragments permits the generation of neo-epitope antibodies to the cleavage site, which can be used to detect ongoing cartilage degradation in patients with arthritic disease, an important adjunct in monitoring disease progression, active disease, and efficacy of treatment. PMID: 14660626 [PubMed - indexed for MEDLINE] > http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=16146751&query_hl=7&itool=pubmed_docsum > ... [quoted text clipped - 52 lines] > > PMID: 16146751 [PubMed - in process] Looks like glucosamine sulfate reduces MMP-13s and thus help minimize damage in arthritis. Sorry this is so technical but it seems to clarify the benefits of glucosamine and chondroitin sulfate. jack n dalton Am J Vet Res. 2005 Nov;66(11):1861-9. Related Articles, Links Effects of glucosamine and chondroitin sulfate on mediators of osteoarthritis in cultured equine chondrocytes stimulated by use of recombinant equine interleukin-1beta. Neil KM, Orth MW, Coussens PM, Chan PS, Caron JP. Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing 48824, USA. OBJECTIVE: To determine whether glucosamine and chondroitin sulfate (CS) at concentrations approximating those achieved in plasma by oral administration would influence gene expression of selected mediators of osteoarthritis in cytokine-stimulated equine articular chondrocytes. SAMPLE POPULATION: Samples of grossly normal articular cartilage obtained from the metacarpophalangeal joint of 13 horses. PROCEDURE: Equine chondrocytes in pellet culture were stimulated with a subsaturating dose of recombinant equine interleukin (reIL)-1beta. Effects of prior incubation with glucosamine (2.5 to 10.0 microg/mL) and CS (5.0 to 50.0 microg/mL) on gene expression of matrix metalloproteinase (MMP)-1, -2, -3, -9, and -13; aggrecanase 1 and 2; inducible nitric oxide synthase (iNOS); cyclooxygenase (COX)-2; nuclear factor kappaB; and c-Jun-N-terminal kinase (JNK) were assessed by use of a quantitative real-time polymerase chain reaction assay. RESULTS: Glucosamine at a concentration of 10 microg/mL significantly reduced reIL-1beta-induced mRNA expression of MMP-13, aggrecanase 1, and JNK. Reductions in cytokine-induced expression were also observed for iNOS and COX-2. Chondroitin sulfate had no effect on gene expression at the concentrations tested. CONCLUSIONS AND CLINICAL RELEVANCE: Concentrations of glucosamine similar to those achieved in plasma after oral administration in horses exerted pretranslational regulation of some mediators of osteoarthritis, an effect that may contribute to the cartilage-sparing properties of this aminomonosaccharide. Analysis of results of this study indicated that the influence of CS on pretranslational regulation of these selected genes is limited or lacking. PMID: 16334941 [PubMed - indexed for MEDLINE] This article suggests that since we know that MMPs do the actual damage that reducing them a tad might help. I have found that a number common meds and supplements (especially certain families of flavonoids) have been shown to reduce these specific MMPs.(MMP-1, MMP-2, MMP-3, MMP-9, MMP-13) Taking the correct ones to reduce a specific MMP should be quite harmless and helpful. jack n dalton Ann Anat. 2005 Nov;187(5-6):473-85. Related Articles, Links Pathomechanisms of cartilage destruction by mechanical injury. Kurz B, Lemke AK, Fay J, Pufe T, Grodzinsky AJ, Schunke M. Anatomisches Institut der Christian-Albrechts-Universitat zu Kiel, Olshausenstrasse 40, D-24098, Kiel, Germany Mechanical injury is considered to be a major inductor of articular cartilage destruction and therefore a risk factor for the development of secondary osteoarthritis. Mechanical injury induces damage to the tissue matrix directly or mediated by chondrocytes via expression of matrix-degrading enzymes and reduction of biosynthetic activity. As a consequence the mechanical properties of cartilage change. Some of the pathomechanisms of mechanical injury have already been uncovered by the use of a broad range of in vitro-models. They demonstrate that mechanical injury induces tissue swelling and decrease in both the compressive and shear stiffness of articular cartilage, probably due to disruption of the collagen network. Injurious compression induces chondrocyte death by necrosis and apoptosis and the remaining cells decrease their biosynthetic activity. The tissue content of proteoglycans also decreases with time in injured cartilage, and the tissue loses its ability to respond to physiological levels of mechanical stimulation with an increase in biosynthesis. Immature cartilage seems to be more vulnerable to injurious compression than more mature tissue. The expression of several matrix-degrading enzymes like ADAM-TS5 and matrix-metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-9, MMP-13) is increased after injury and may in part be regulated by an autocrine vascular endothelial growth factor (VEGF)-dependent signalling pathway. Apoptosis seems to be mediated by caspase activity and reactive oxygen species. For that reason activation of antioxidative defense mechanisms as well as the inhibition of angiogenetic factors and MMPs might be key regulators in the mechanically induced destruction of cartilage and might be suggested as potential therapeutic interventions. This review summarizes some of the most important data from in vitro injury studies dealing with the pathomechanisms of cartilage destruction. Publication Types: a.. Review PMID: 16320827 [PubMed - indexed for MEDLINE] I was very happy to find that EGCG (polyphenol epigallocatechin-3-gallate) a flavonoid in green tea does the job quite well. I think it would be very STUPID to drink MASSIVE amounts of green tea. HOWEVER!! Taking some GOOD QUALITY GREEN/WHITE TEA EXTRACT would seem to be a good idea. I must say this because I have had some complaints in the past about the quantity of green tea that on had to drink to get this benefit. jack n dalton J Pharmacol Exp Ther. 2004 Feb;308(2):767-73. Epub 2003 Nov 4. Green tea polyphenol epigallocatechin-3-gallate (EGCG) differentially inhibits interleukin-1 beta-induced expression of matrix metalloproteinase-1 and -13 in human chondrocytes. Ahmed S, Wang N, Lalonde M, Goldberg VM, Haqqi TM. Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4946, USA. Interleukin-1beta (IL-1beta)-induced inflammatory response in arthritic joints include the enhanced expression and activity of matrix metalloproteinases (MMPs), and their matrix degrading activity contribute to the irreversible loss of cartilage and may also be associated with sustained chronic inflammation. We have earlier shown that green tea (Camellia sinensis) polyphenol epigallocatechin-3-gallate (EGCG) was non-toxic to human chondrocytes [Singh R, Ahmed S, Islam N, Goldberg VM, and Haqqi TM (2002) Arthritis Rheum 46: 2079-2086] and inhibits the expression of inflammatory mediators in arthritic joints [Haqqi TM, Anthony DD, Gupta S, Ahmed N, Lee MS, Kumar GK, and Mukhtar H (1999) Proc Natl Acad Sci USA 96: 4524-4529]. Here we show that EGCG at micromolar concentrations was highly effective in inhibiting the IL-1beta-induced glycosaminoglycan (GAG) release from human cartilage explants in vitro. EGCG also inhibited the IL-1beta-induced mRNA and protein expression of MMP-1 and MMP-13 in human chondrocytes. Importantly, EGCG showed a differential, dose-dependent inhibitory effect on the expression and activity of MMP-13 and MMP-1. A similar differential dose-dependent inhibition of transcription factors NF-kappaB and AP-1 by EGCG was also noted. These results for the first time demonstrate a differential dose-dependent effect of EGCG on the expression and activity of MMPs and on the activities of transcription factors NF-kappaB and AP-1 and provide insights into the molecular basis of the reported anti-inflammatory effects of EGCG. These results also suggest that EGCG or compounds derived from it may be therapeutically effective inhibitors of IL-1beta-induced production of matrix-degrading enzymes in arthritis. PMID: 14600251 [PubMed - indexed for MEDLINE] > This article suggests that since we know that MMPs do the actual damage > that reducing them a tad might help. [quoted text clipped - 58 lines] > > PMID: 16320827 [PubMed - indexed for MEDLINE] One of the most potent MMP inhibitors of MMP-13 and MMP-3s is curcumin. Since it is poorly absorbed taking some black pepper extract will increase this by 2000%. The LEF www.lef.org includes some black pepper extract with their Super Curcumin product. Caution must be used because it could increase other medication concentrations. I take it during a window that is 5 hrs after morning meds/supplements and 5 hrs before evening meds/supplements. jack n dalton 1: Matrix Biol 2002 Apr;21(3):251-62 Inhibition of interleukin-1-stimulated MAP kinases, activating protein-1 (AP-1) and nuclear factor kappa B (NF-kappa B) transcription factors down-regulates matrix metalloproteinase gene expression in articular chondrocytes. Liacini A, Sylvester J, Li WQ, Zafarullah M. Departement de Medecine and Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Hopital Notre-Dame du CHUM, 1560 Sherbrooke est, Montreal, Quebec, Canada H2L 4M1. Interleukin-1 (IL-1), the main cytokine instigator of cartilage degeneration in arthritis, induces matrix metalloproteinase-3 (MMP-3) and MMP-13 RNA and protein in chondrocytes. The molecular mechanisms of this induction were investigated with specific inhibitors of mitogen-activated protein kinase (MAPK) signaling pathways and activating protein (AP-1) and nuclear factor kappa B (NF-kappa B) transcription factors. IL-1 rapidly induced the activation of extracellular-signal regulated kinase (ERK), protein 38 (p38) and c-Jun N-terminal kinase (JNK) MAPKs in the first-passage human femoral head OA chondrocytes. The ERK-MAPK pathway inhibitor, PD98059, attained 46-53% (MMP-3) and 59-66% (MMP-13) inhibition of RNA induction in human OA and 47-52% (MMP-3) and 69-73% (MMP-13) inhibition in bovine chondrocytes. U0126 conferred 37-77% (MMP-3) and 43-73% (MMP-13) suppression in human and 77-100% (MMP-3) and 96-100% (MMP-13) in bovine chondrocytes. P38 and JNK inhibitor, SB203580 caused 35-37% reduction of MMP-3 and MMP-13 RNA in human and 36-46% (MMP-3) and 60-88% (MMP-13) in bovine chondrocytes. Inhibitor of JNK, AP-1 and NF-kappa B, curcumin, achieved 48-99% suppression of MMP-3 and 45-97% of MMP-13 in human and 8-100% (MMP-3) and 32-100% (MMP-13) in bovine chondrocytes. NF-kappaB inhibitor, pyrrolidine dithiocarbamate yielded 83-84% reduction of MMP-3 and 38-55% for MMP-13 in human chondrocytes. In bovine chondrocytes, the induction decreased by 54-64% for MMP-3 and 74-93% for MMP-13 RNA. These results suggest the involvement of MAPKs, AP-1 and NF-kappa B transcription factors in the IL-1 induction of MMPs in chondrocytes. Inhibition of IL-1 signal transduction by these agents could be useful for reducing cartilage resorption by MMPs in arthritis. PMID: 12009331 [PubMed - indexed for MEDLINE] .. . : Planta Med. 1998 May;64(4):353-6. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS. Department of Pharmacology, St. John's Medical College, Bangalore, India. The medicinal properties of curcumin obtained from Curcuma longa L. cannot be utilised because of poor bioavailability due to its rapid metabolism in the liver and intestinal wall. In this study, the effect of combining piperine, a known inhibitor of hepatic and intestinal glucuronidation, was evaluated on the bioavailability of curcumin in rats and healthy human volunteers. When curcumin was given alone, in the dose 2 g/kg to rats, moderate serum concentrations were achieved over a period of 4 h. Concomitant administration of piperine 20 mg/kg increased the serum concentration of curcumin for a short period of 1-2 h post drug. Time to maximum was significantly increased (P < 0.02) while elimination half life and clearance significantly decreased (P < 0.02), and the bioavailability was increased by 154%. On the other hand in humans after a dose of 2 g curcumin alone, serum levels were either undetectable or very low. Concomitant administration of piperine 20 mg produced much higher concentrations from 0.25 to 1 h post drug (P < 0.01 at 0.25 and 0.5 h; P < 0.001 at 1 h), the increase in bioavailability was 2000%. The study shows that in the dosages used, piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no adverse effects. Publication Types: Clinical Trial "> >> This article suggests that since we know that MMPs do the actual damage >> that reducing them a tad might help. [quoted text clipped - 58 lines] >> >> PMID: 16320827 [PubMed - indexed for MEDLINE] Celebrex is good at lowering MMP-3s as well as those things that start the whole inflammation cascade. Rheumatol Int. 2003 Jul 26 [Epub ahead of print] Inhibitory effect of cyclo-oxygenase-2 inhibitor on the production of matrix metalloproteinases in rheumatoid fibroblast-like synoviocytes. Cha HS, Ahn KS, Jeon CH, Kim J, Koh EM. Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Kangnam-Ku, Seoul 135-710, Korea. Cyclo-oxygenase (COX)-2 has been associated with inflammation in rheumatoid arthritis (RA), but its role in joint destruction remains unclear. In this study, we investigated the effect on cultured rheumatoid fibroblast-like synoviocytes (FLS) of the selective COX-2 inhibitor celecoxib on the expression of matrix metalloproteinases (MMPs), which play an important role in tissue degradation and angiogenesis in rheumatoid synovium. Treatment with nontoxic doses of celecoxib resulted in dose-dependent inhibition of MMP-1, -2, and -3 secretion from FLS when measured by enzyme-linked immunosorbent assay. Celecoxib suppressed proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-1beta) induced augmentation of the gelatinolytic activity on zymography. These results suggest that COX-2 inhibitors might influence matrix degradation or angiogenesis in RA by downregulating the expression of various MMPs in rheumatoid FLS. PMID: 12898179 [PubMed - as supplied by publisher] 1: Arthritis Rheum. 2002 Jun;46(6):1544-53. Pathologic indicators of degradation and inflammation in human osteoarthritic cartilage are abrogated by exposure to n-3 fatty acids. Curtis CL, Rees SG, Little CB, Flannery CR, Hughes CE, Wilson C, Dent CM, Otterness IG, Harwood JL, Caterson B. Connective Tissue Biology Laboratories, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3US, Wales, UK. OBJECTIVE: To determine if n-3 polyunsaturated fatty acid (PUFA) supplementation (versus treatment with n-6 polyunsaturated or other fatty acid supplements) affects the metabolism of osteoarthritic (OA) cartilage. METHODS: The metabolic profile of human OA cartilage was determined at the time of harvest and after 24-hour exposure to n-3 PUFAs or other classes of fatty acids, followed by explant culture for 4 days in the presence or absence of interleukin-1 (IL-1). Parameters measured were glycosaminoglycan release, aggrecanase and matrix metalloproteinase (MMP) activity, and the levels of expression of messenger RNA (mRNA) for mediators of inflammation, aggrecanases, MMPs, and their natural tissue inhibitors (tissue inhibitors of metalloproteinases [TIMPs]). RESULTS: Supplementation with n-3 PUFA (but not other fatty acids) reduced, in a dose-dependent manner, the endogenous and IL-1-induced release of proteoglycan metabolites from articular cartilage explants and specifically abolished endogenous aggrecanase and collagenase proteolytic activity. Similarly, expression of mRNA for ADAMTS-4, MMP-13, and MMP-3 (but not TIMP-1, -2, or -3) was also specifically abolished with n-3 PUFA supplementation. In addition, n-3 PUFA supplementation abolished the expression of mRNA for mediators of inflammation (cyclooxygenase 2, 5-lipoxygenase, 5-lipoxygenase-activating protein, tumor necrosis factor alpha, IL-1alpha, and IL-1beta) without affecting the expression of message for several other proteins involved in normal tissue homeostasis. CONCLUSION: These studies show that the pathologic indicators manifested in human OA cartilage can be significantly altered by exposure of the cartilage to n-3 PUFA, but not to other classes of fatty acids. PMID: 12115185 [PubMed - indexed for MEDLINE] " As stated earlier MMP-9s also get recruited into doing damage in arthritis. They are very good at cutting "things up" into easy to digest pieces. So it is a good idea to lower them. Things that reduce MMP-9s (AKA gelatinase B) VIT D3 .......................................................REDUCES MMP-9s RESVERATROL (Grape Skin Extract)..... ...REDUCES MMP-9s GREEN TEA EXTRACT(EGCGs)............... REDUCES MMP-9s ALPHA LIPOIC ACID (R-lipoic/ R-Dihdro-LipoicAcid) ... REDUCES MMP-9s NAC N-Acetyl-L-Cysteine .............................REDUCES MMP-9s STATIN DRUGS (i.e Zocor, Lipitor..............REDUCES MMP-9s Omega-3s (ie Fish oil)(walnut oil).................REDUCES MMP-9s Minocycline/Doxycycline...............................REDUCES MMP-9s Curcumin........................................................REDUCES MMP-9s Pycnogenol (Pine bark extract)...................REDUCES MMP-9s Chondroitin sulfate (CS) and CS plus glucosamine sulfate (GS) ..REDUCES MMP-9s jack, this is pretty intriguing stuff. Thanks for sharing it. johnie > As stated earlier MMP-9s also get recruited into doing damage in arthritis. > They are very good at cutting "things up" into easy to digest pieces. [quoted text clipped - 26 lines] > Chondroitin sulfate (CS) and CS plus glucosamine sulfate (GS) ..REDUCES > MMP-9s >Inhibitory effect of cyclo-oxygenase-2 inhibitor on the production of matrix >metalloproteinases in rheumatoid fibroblast-like synoviocytes. Jack, do you know if Celebrex is classified as NSAID as well as a Cox-2 drug? My stomach reacts big time to NSAIDS and my RD said to stop them, my GP suggested Celebrex which I took years ago without problems, but I chose not to fill that script until I see my RD end of the month. --- Joan > Jack, do you know if Celebrex is classified as NSAID as well as a Cox-2 drug? Joan, Im not Jack but can tell you that celebrex is a NSAID. johnie >Joan, Im not Jack but can tell you that celebrex is a NSAID. Thank you, Johnie. --- Joan Y put this on the NG The average person does'nt understand it??? >Y put this on the NG The average person does'nt understand it??? Ken My posting are only for above average, highly motivated, intelligent people on a quest for a wide variety of helpful medical information. I would be glad to clarify and explain some things. If you just look at the FINDINGS and CONCLUSIONS/RESULTS sections you will get the essence without needing to know the details. My main point is that there are some VERY SIMPLE ways to lower critical MMP levels without killing yourself in the process. This MMP stuff is very new and I could elaborate on the other fantastic benefits gained by lowering some MMPs but I will save that for another day and maybe another support group. MMPs are the LAST step in the destructive process. It would be GREAT if there were effective-safe ways to reduce other substances that activate/create them. jack n dalton >Y put this on the NG The average person does'nt understand it??? |
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