nach oben

Drugs & Aging

Erschienen in:

01.02.2001 | Leading Article

The Clinical Potential of Matrix Metalloproteinase Inhibitors in the Rheumatic Disorders

verfasst von: Sarah Elliott, Professor Tim Cawston

Erschienen in: Drugs & Aging | Ausgabe 2/2001

Einloggen, um Zugang zu erhalten

Abstract

Rheumatoid arthritis (RA) and osteoarthritis are chronic diseases that result in cartilage degradation and loss of joint function. Currently available drugs are predominantly directed towards the control of pain and/or the inflammation associated with joint synovitis but they do little to reduce joint destruction. In the future, it will be important to have drugs that prevent the structural damage caused by bone and cartilage breakdown.

In this review, we will outline the structure and function of cartilage and the key features of matrix metalloproteinases (MMPs), enzymes involved in joint destruction. We will present evidence for the role of MMPs in RA and osteoarthritis, and describe the potential of synthetic inhibitors to control MMP activity and so prevent joint destruction.

MMPs are able to cleave all components of the cartilage matrix. Regulation of MMPs is aberrant in osteoarthritis and RA, and MMPs have been implicated in the collagen breakdown that contributes to joint destruction in these diseases. Synthetic MMP inhibitors have been developed. In animal models of osteoarthritis and/or RA, these agents have shown chondroprotective effects. However, results from clinical trials in RA have been equivocal, with some studies being terminated because of lack of efficacy or safety concerns. Nevertheless, this approach remains promising. Increased understanding of the structure, regulation and function of individual MMPs may lead to more effective strategies, and approaches aimed at multiple steps of the pathogenesis of arthritis may be needed to break the chronic cycle of joint destruction.

Conaghan PG, Brooks P. Disease-modifying antirheumatic drugs, including methotrexate, gold, antimalarials, and D-penicillamine. Curr Opin Rheumatol 1995; 7(3): 167–73PubMedCrossRef

Hardingham TE, Fosang AJ. Proteoglycans: many forms and any functions. FASEB J 1992; 6: 861–70PubMed

Muir H. The chondrocyte, architect of cartilage: biomechanics, structure, function and molecular biology of cartilage matrix macromolecules. Bioessays 1995; 17: 1039–48PubMedCrossRef

Dingle JT, Page TDP, King B, et al. In vivo studies of articular tissue damage mediated by catabolin/interleukin 1. Ann Rheum Dis 1987; 46: 527–33PubMedCrossRef

Page-Thomas DP, King B, Stephens T, et al. In vivo studies of cartilage regeneration after damage induced by catabolin/interleukin-1. Ann Rheum Dis 1991; 50: 75–80PubMedCrossRef

Fell HB, Barratt ME, Welland H, et al. The capacity of pig articular cartilage in organ culture to regenerate after breakdown induced by complement-sufficient antiserum to pig erythrocytes. Calcif Tissue Res 1976; 20(1): 3–21PubMedCrossRef

van der Rest M, Garrone R. Collagen family of proteins. FASEB J 1991; 5(13): 2814–23PubMed

Jubb RW, Fell HB. The breakdown of collagen by chondrocytes. J Pathol 1980; 130: 159–62PubMedCrossRef

Cawston TE. Proteinases and inhibitors. Br Med Bull 1995; 51: 385–401PubMed

10.

Birkedal-Hansen H, Moore WGI, Bodden MK, et al. Matrix metalloproteinases: a review. Crit Rev Oral Biol Med 1993; 4: 197–250PubMed

11.

Van Wart HE, Birkedal-Hansen H. The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc Natl Acad Sci U S A 1990; 87: 5578–82PubMedCrossRef

12.

Henriet P, Blavier L, DeClerck YA. Tissue inhibitors of metalloproteinases (TIMP) in invasion and proliferation. APMIS 1999; 107: 111–9PubMedCrossRef

13.

Collier IE, Wilhelm SM, Eisen AZ, et al. H-ras oncogene-transformed human bronchial epithelial cells (TBE-1) secrete a single metalloprotease capable of degrading basement membrane collagen. J Biol Chem 1988; 263(14): 6579–87PubMed

14.

Wilhelm SM, Collier IE, Marmer BL, et al. SV40-transformed human lung fibroblasts secrete a 92-kDa type IV collagenase which is identical to that secreted by normal human macrophages. J Biol Chem 1989; 264(29): 17213–21PubMed

15.

Allan JA, Docherty AJP, Barker PJ, et al. Binding of gelatinases A and B to type-I collagen and other matrix components. Biochem J 1995; 309: 299–306PubMed

16.

Sato H, Takino T, Okada Y, et al. A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 1994; 370: 61–5PubMedCrossRef

17.

Sato H, Kinoshita T, Takino T, et al. Activation of a recombinant membrane type 1-matrix metalloproteinase (MT1-MMP) by furin and its interaction with tissue inhibitor of metalloproteinases (TTMP)-2. FEBS Lett 1996; 393(1): 101–4PubMedCrossRef

18.

Pei D, Weiss SJ. Furin-dependent intracellular activation of the human stromelysin-3 zymogen. Nature 1995; 375(6528): 244–7PubMedCrossRef

19.

Matrisian LM. The matrix-degrading metalloproteinases. Bioessays 1992; 14: 455–63PubMedCrossRef

20.

Clark IM, Rowan A, Cawston TE. Matrix metalloproteinase inhibitors in the treatment of arthritis. Curr Opin Anti-inflamm Immunomod Invest Drugs 2000; 2(1): 16–25

21.

Shingleton WD, Hodges DJ, Brick P, et al. Collagenase: a key enzyme in collagen turnover. Biochem Cell Biol 1996; 74(6): 759–75PubMedCrossRef

22.

Welgus HG, Jeffrey JJ, Stricklin GP, et al. Characteristics of the action of human skin fibroblast collagenase on fibrillar collagen. J Biol Chem 1980; 255(14): 6806–13PubMed

23.

Hasty KA, Jeffrey JJ, Hibbs MS, et al. The collagen substrate specificity of human neutrophil collagenase. J Biol Chem 1987; 262(21): 10048–52PubMed

24.

Knauper V, Lopez-Otin C, Smith B, et al. Biochemical characterisation of human collagenase-3. J Biol Chem 1996; 271: 1544–50PubMedCrossRef

25.

Cawston TE, Rowan AD. Prevention of cartilage breakdown by matrix metalloproteinase inhibition: a realistic therapeutic target? Br J Rheumatol 1998; 37: 353–6PubMedCrossRef

26.

Clark IM, Powell LK, Ramsey S, et al. The measurement of collagenase, tissue inhibitor of metalloproteinases (TIMP), and collagenase-TIMP complex in synovial fluids from patients with osteoarthritis and rheumatoid arthritis. Arthritis Rheum 1993; 36: 372–9PubMedCrossRef

27.

Mort JS, Dodge GR, Roughley PJ, et al. Direct evidence for active metalloproteinases mediating matrix degradation in interleukin 1-stimulated human articular cartilage. Matrix 1993; 13(2): 95–102PubMedCrossRef

28.

Dodge GR, Pidoux I, Poole AR. The degradation of type II collagen in rheumatoid arthritis: an immunoelectron microscopic study. Matrix 1991; 11(5): 330–8PubMedCrossRef

29.

McCachren SS. Expression of metalloproteinases and metalloproteinase inhibitor in human arthritic synovium. Arthritis Rheum 1991; 34(9): 1085–93PubMedCrossRef

30.

Brinckerhoff CE. Joint destruction in arthritis: metalloproteinases in the spotlight. Arthritis Rheum 1991; 34(9): 1073–5PubMedCrossRef

31.

Arner EC, Pratta MA, Trzaskos JM, et al. Generation and characterization of aggrecanase — a soluble, cartilage-derived aggrecan-degrading activity. J Biol Chem 1999; 274(10): 6594–601PubMedCrossRef

32.

Abbaszade I, Liu RQ, Yang F, et al. Cloning and characterization of ADAMTS11, an aggrecanase from the ADAMTS family. J Biol Chem 1999; 274(33): 23443–50PubMedCrossRef

33.

Billington CJ, Clark IM, Cawston TE. An aggrecan-degrading activity associated with chondrocyte membranes. Biochem J 1998; 336(1): 207–12PubMed

34.

Amour A, Slocombe PM, Webster A, et al. TNF-α converting enzyme (TACE) is inhibited by TIMP-3. FEBS Lett 1998; 435(1): 39–44PubMedCrossRef

35.

Brennan FM, Browne KA, Green PA, et al. Reduction of serum matrix metalloproteinase 1 and matrix metalloproteinase 3 in rheumatoid arthritis patients following anti-tumour necrosis factor-a (cA2) therapy. Br J Rheumatol 1997; 36(6): 643–50PubMedCrossRef

36.

Lipsky P, St. Clair W, Furst D, et al. 54 week clinical and radiographic results from the ATTRACT trial: a phase III study of infliximab (Remicade™) in patients with active RA despite methotrexate [abstract]. Arthritis Rheum 1999; 42Suppl. 11: S401

37.

Elliott S, Rowan A, Carrère S, et al. Esculetin inhibits cartilage resorption induced by IL-1 α in combination with OSM. Ann Rheum Dis 2001; 60: 158–65PubMedCrossRef

38.

Martel-Pelletier J, Mineau F, Tardif G, et al. Tenidap reduces the level of interleukin 1 receptors and collagenase expression in human arthritic synovial fibroblasts. J Rheumatol 1996; 23: 24–31PubMed

39.

Beckett RP, Davidson AH, Drummond AH, et al. Recent advances in matrix metalloproteinase inhibitor research. Drug Disc Today 1995; 1: 16–26CrossRef

40.

Bottomley KM, Johnson WH, Walter DS. Matrix metalloproteinase inhibitors in arthritis. J Enzyme Inhib 1998; 13(2): 79–101PubMedCrossRef

41.

Martel-Pelletier, Pelletier JP. Wanted: the collagenase responsible for the destruction of the collage network in human cartilage. Br J Rheumatol 1996; 35(9): 818–20PubMedCrossRef

42.

Nemunaitis J, Poole C, Primrose J, et al. Combined analysis of studies of the effects of the matrix metalloproteinase inhibitor marimastat on serum tumor markers in advanced cancer: selection of a biologically active and tolerable dose for longer-term studies. Clin Cancer Res 1998; 4(5): 1101–9PubMed

43.

Shapiro SD. Mighty mice: transgenic technology ‘knocks out’ questions of metalloproteinase function. Matrix Biol 1997; 15: 527–33PubMedCrossRef

44.

Black RA, Rauch CT, Kozlosky CJ, et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 1997; 385(6618): 729–33PubMedCrossRef

45.

Konttinen YT, Ceponis A, Takagi M, et al. New collagenolytic enzymes cascade identified at the pannus-hard tissue junction in rheumatoid arthritis: destruction from above. Matrix Biol 1998; 17(8–9): 585–601PubMedCrossRef

46.

Knauper V, Will H, Lopez-Otin C, et al. Cellular mechanisms for human procollagenase-3 (MMP-13) activation: evidence that MT1-MMP (MMP-14) and gelatinase a (MMP-2) are able to generate active enzyme. J Biol Chem 1996; 271(29): 17124–31PubMedCrossRef

47.

Brewster M, Lewis EJ, Wilson KL, et al. Ro 32-3555, an orally active collagenase selective inhibitor, prevents structural damage in the STR/ORT mouse model of osteoarthritis. Arthritis Rheum 1998; 41(9): 1639–44PubMedCrossRef

48.

Greenwald RA. Treatment of destructive arthritic disorders with MMP inhibitors: potential role of tetracyclines. Ann NY Acad Sci 1994; 732: 181–98PubMedCrossRef

49.

Greenwald RA, Golub LM, Ramamurthy NS, et al. In vitro sensitivity of the three mammalian collagenases to tetracycline inhibition: relationship to bone and cartilage degradation. Bone 1998; 22(1): 33–8PubMedCrossRef

50.

Cawston TE. Metalloproteinase inhibitors and the prevention of connective tissue breakdown. Pharmacol Ther 1996; 70(3): 163–82PubMedCrossRef

51.

Shaw, T. Inhibition of matrix metalloproteinases in rheumatoid arthritis. In: Firestein GS, Panayi GS, Wollheim F, editors. Rheumatoid arthritis. Oxford: Oxford University Press, 2000: 551–61

52.

Butler GS, Hutton M, Wattam BA, et al. The specificity of TIMP-2 for matrix metalloproteinases can be modified by single amino acid mutations. J Biol Chem 1992; 274(29): 20391–6CrossRef

Titel: The Clinical Potential of Matrix Metalloproteinase Inhibitors in the Rheumatic Disorders
verfasst von: Sarah Elliott
Professor Tim Cawston
Publikationsdatum: 01.02.2001
Verlag: Springer International Publishing
Erschienen in: Drugs & Aging / Ausgabe 2/2001
Print ISSN: 1170-229X
Elektronische ISSN: 1179-1969
DOI: https://doi.org/10.2165/00002512-200118020-00002

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Reizdarmsyndrom: Diäten wirksamer als Medikamente

29.04.2024 Reizdarmsyndrom Nachrichten

Bei Reizdarmsyndrom scheinen Diäten, wie etwa die FODMAP-arme oder die kohlenhydratreduzierte Ernährung, effektiver als eine medikamentöse Therapie zu sein. Das hat eine Studie aus Schweden ergeben, die die drei Therapieoptionen im direkten Vergleich analysierte.

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

26.04.2024 Hüft-TEP Nachrichten

Ob bei einer Notfalloperation nach Schenkelhalsfraktur eine Hemiarthroplastik oder eine totale Endoprothese (TEP) eingebaut wird, sollte nicht allein vom Alter der Patientinnen und Patienten abhängen. Auch über 90-Jährige können von der TEP profitieren.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

25.04.2024 Allergien und Intoleranzreaktionen Nachrichten

Insektenstiche sind bei Erwachsenen die häufigsten Auslöser einer Anaphylaxie. Einen wirksamen Schutz vor schweren anaphylaktischen Reaktionen bietet die allergenspezifische Immuntherapie. Jedoch kommt sie noch viel zu selten zum Einsatz.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 2/2001

Epidemiology of Over-the-Counter Drug Use in Community Dwelling Elderly

Contemporary Management of Chronic Stable Angina

Status Epilepticus in Older Patients

Optimising Treatment for Resectable Rectal Cancer

Dry Eye in the Elderly