Download PDF
Planta Med 2009; 75(12): 1319-1325
DOI: 10.1055/s-0029-1185668
Pharmacology
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

Phytomedicines Prepared from Arnica Flowers Inhibit the Transcription Factors AP-1 and NF-κB and Modulate the Activity of MMP1 and MMP13 in Human and Bovine Chondrocytes[*]

Christoph Jäger1 , Andrea Hrenn1 , Jörn Zwingmann2 , Andreas Suter3 , Irmgard Merfort1
  • 1Institute for Pharmaceutical Sciences, Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, Freiburg, Germany
  • 2Department of Orthopaedics and Trauma Surgery, University Hospital Freiburg, Freiburg, Germany
  • 3Bioforce AG, Roggwil, Switzerland
Further Information

Publication History

received January 6, 2009 revised March 1, 2009

accepted March 26, 2009

Publication Date:
08 May 2009 (online)

Also available at
    Permissions and Reprints

Abstract

Arnica preparations have long been used for the symptomatic treatment of rheumatic complaints and recent clinical trials have demonstrated the beneficial effects of Arnica preparations in the treatment of osteoarthritis (OA). The efficacy of Arnica is presumed to be mainly due to its anti-inflammatory properties and inhibition of the transcription factor NF-κB. Here we provide further insights into its molecular mode of action. Arnica preparations suppress MMP1 and MMP13 mRNA levels in bovine and human articular chondrocytes in a concentration-dependent manner and in a low concentration range. This suppression may be due to inhibition of DNA binding of the transcription factors AP-1 and NF-κB. Interestingly, sesquiterpene lactones present in the preparations were always more active than the pure compounds, demonstrating the advantage of using plant preparations.

Key words

Arnica montana - Asteraceae - sesquiterpene lactones - AP‐1 - NF‐κB - MMP1 and MMP13 - osteoarthritis

1 Dedicated to Prof. Dr. G. Willuhn on the occasion of his 75th birthday.

References

  • 1 Roach H I, Aigner T, Soder S, Haag J, Welkerling H. Pathobiology of osteoarthritis: pathomechanisms and potential therapeutic targets.  Curr Drug Targets. 2007;  8 271-282
    CrossrefPubMedSearch in Google Scholar
  • 2 Goldring M B. Update on the biology of the chondrocyte and new approaches to treating cartilage diseases.  Best Pract Res Clin Rheumatol. 2006;  20 1003-1025
    CrossrefPubMedSearch in Google Scholar
  • 3 Aigner T, Soder S, Gebhard P M, McAlinden A, Haag J. Mechanisms of disease: role of chondrocytes in the pathogenesis of osteoarthritis – structure, chaos and senescence.  Nat Clin Pract Rheumatol. 2007;  3 391-399
    CrossrefPubMedSearch in Google Scholar
  • 4 Pardo A, Selman M. MMP‐1: the elder of the family.  Int J Biochem Cell Biol. 2005;  37 283-288
    CrossrefPubMedSearch in Google Scholar
  • 5 Tardif G, Reboul P, Pelletier J P, Martel-Pelletier J. Ten years in the life of an enzyme: the story of the human MMP‐13 (collagenase-3).  Mod Rheumatol. 2004;  14 197-204
    PubMedSearch in Google Scholar
  • 6 Yan C, Boyd D D. Regulation of matrix metalloproteinase gene expression.  J Cell Physiol. 2007;  211 19-26
    CrossrefPubMedSearch in Google Scholar
  • 7 Rowan A D, Young D A. Collagenase gene regulation by pro-inflammatory cytokines in cartilage.  Front Biosci. 2007;  12 536-550
    CrossrefPubMedSearch in Google Scholar
  • 8 Otero M, Goldring M B. Cells of the synovium in rheumatoid arthritis. Chondrocytes.  Arthritis Res Ther. 2007;  9 220
    CrossrefPubMedSearch in Google Scholar
  • 9 Knuesel O, Weber M, Suter A. Arnica montana gel in osteoarthritis of the knee: An open, multicenter clinical trial.  Adv Ther. 2002;  19 209-218
    CrossrefPubMedSearch in Google Scholar
  • 10 Widrig R, Suter A, Saller R, Melzer J. Choosing between NSAID and Arnica for topical treatment of hand osteoarthritis in a randomised, double-blind study.  Rheumatol Int. 2007;  27 585-591
    CrossrefPubMedSearch in Google Scholar
  • 11 Merfort I. Arnica: new insights on the molecular mode of action of a traditional medicinal plant.  Forsch Komplementarmed Klass Naturheilkd. 2003;  10 (Suppl. 1) 45-48
    CrossrefPubMedSearch in Google Scholar
  • 12 Klaas C A, Wagner G, Laufer S, Sosa S, Della L R, Bomme U, Pahl H L, Merfort I. Studies on the anti-inflammatory activity of phytopharmaceuticals prepared from Arnica flowers.  Planta Med. 2002;  68 385-391
    Thieme ConnectPubMedSearch in Google Scholar
  • 13 Lyss G, Schmidt T J, Merfort I, Pahl H L. Helenalin, an anti-inflammatory sesquiterpene lactone from Arnica, selectively inhibits transcription factor NF-kappaB.  Biol Chem. 1997;  378 951-961
    PubMedSearch in Google Scholar
  • 14 Lyss G, Knorre A, Schmidt T J, Pahl H L, Merfort I. The anti-inflammatory sesquiterpene lactone helenalin inhibits the transcription factor NF-kappaB by directly targeting p65.  J Biol Chem. 1998;  273 33508-33516
    CrossrefPubMedSearch in Google Scholar
  • 15 Lyss G, Schmidt T J, Pahl H L, Merfort I. Anti-inflammatory activity of Arnica tincture (DAB 1998) using the transcription factor NF-κB as molecular target.  Pharm Pharmacol Lett. 1999;  9 5-8
    PubMedSearch in Google Scholar
  • 16 Wagner S, Suter A, Merfort I. Skin penetration studies of Arnica preparations and of their sesquiterpene lactones.  Planta Med. 2004;  70 897-903
    Thieme ConnectPubMedSearch in Google Scholar
  • 17 Wagner S, Merfort I. Skin penetration behaviour of sesquiterpene lactones from different Arnica preparations using a validated GC‐MSD method.  J Pharm Biomed Anal. 2007;  43 32-38
    CrossrefPubMedSearch in Google Scholar
  • 18 Willuhn G, Leven W. Zur qualitativen und quantitativen Analyse der Sesquiterpenlactone von Arnikablüten DAB 9.  Pharm Ztg Wiss. 1991;  136 32-39
    PubMedSearch in Google Scholar
  • 19 Lindenmeyer M T, Hrenn A, Kern C, Castro V, Murillo R, Muller S, Laufer S, Schulte-Mönting J, Siedle B, Merfort I. Sesquiterpene lactones as inhibitors of IL‐8 expression in HeLa cells.  Bioorg Med Chem. 2006;  14 2487-2497
    CrossrefPubMedSearch in Google Scholar
  • 20 Mengshol J A, Vincenti M P, Coon C I, Barchowsky A, Brinckerhoff C E. Interleukin-1 induction of collagenase 3 (matrix metalloproteinase 13) gene expression in chondrocytes requires p38, c-Jun N-terminal kinase, and nuclear factor kappaB: differential regulation of collagenase 1 and collagenase 3.  Arthritis Rheumatol. 2000;  43 801-811
    CrossrefPubMedSearch in Google Scholar
  • 21 Wagner S, Kratz F, Merfort I. In vitro behaviour of sesquiterpene lactones and sesquiterpene lactone-containing plant preparations in human blood, plasma and human serum albumin solutions.  Planta Med. 2004;  70 227-233
    Thieme ConnectPubMedSearch in Google Scholar
  • 22 Garcia-Pineres A J, Lindenmeyer M T, Merfort I. Role of cysteine residues of p65/NF-kappaB on the inhibition by the sesquiterpene lactone parthenolide and N-ethylmaleimide, and on its transactivating potential.  Life Sci. 2004;  75 841-856
    CrossrefPubMedSearch in Google Scholar
  • 23 Ohno S, Im H J, Knudson C B, Knudson W. Hyaluronan oligosaccharides induce matrix metalloproteinase 13 via transcriptional activation of NFkappaB and p38 MAP kinase in articular chondrocytes.  J Biol Chem. 2006;  281 17952-17960
    CrossrefPubMedSearch in Google Scholar
  • 24 Collier S, Ghosh P. Comparison of the effects of non-steroidal anti-inflammatory drugs (NSAIDs) on proteoglycan synthesis by articular cartilage explant and chondrocyte monolayer cultures.  Biochem Pharmacol. 1991;  41 1375-1384
    CrossrefPubMedSearch in Google Scholar
  • 25 Monfort J, Nacher M, Montell E, Vila J, Verges J, Benito P. Chondroitin sulfate and hyaluronic acid (500–730 kda) inhibit stromelysin-1 synthesis in human osteoarthritic chondrocytes.  Drugs Exp Clin Res. 2005;  31 71-76
    PubMedSearch in Google Scholar
  • 26 Pelletier J P, Pelletier J M. DMOAD developments – present and future.  Bull NYU Hospital Joint Diseases. 2007;  65 242-248
    PubMedSearch in Google Scholar

1 Dedicated to Prof. Dr. G. Willuhn on the occasion of his 75th birthday.

Prof. Dr. I. Merfort

Institute for Pharmaceutical Sciences
Department of Pharmaceutical Biology and Biotechnology
University of Freiburg

Stefan-Meier-Str. 19

79104 Freiburg

Germany

Phone: + 49 76 12 03 83 73

Fax: + 49 76 12 03 83 83

Email: irmgard.merfort@pharmazie.uni-freiburg.de

    www.thieme-connect.de/ejournals/toc/plantamedica