Cited by 58Osteoarthritis Treatment and MechanismsProtease and Inhibitor MechanismsProteoglycans and glycosaminoglycans research

Collagen and Aggrecan Degradation Is Blocked in Interleukin-1-Treated Cartilage Explants by an Inhibitor of IκB Kinase through Suppression of Metalloproteinase Expression

Pattoli, Mark A., MacMaster, John F., Gregor, Kurt R., Burke, James R.·2005·The Journal of Pharmacology and Experimental Therapeutics

Abstract

It has previously been shown that BMS-345541 [4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline], a highly-selective inhibitor of IkappaB kinase (IKK), blocks both inflammation and joint destruction in murine collagen-induced arthritis. Although this agent has been shown to inhibit nuclear factor-kappaB-dependent cytokine expression in mice, we examined whether the inhibitor directly inhibits cytokine-driven metalloproteinase expression and cartilage degradation. In SW-1353 human chondrosarcoma cells, BMS-345541 inhibited interleukin-1 (IL-1)-dependent expression of matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13 in a concentration-dependent manner. IL-1 treatment failed to induce and BMS-345541 did not inhibit the expression of aggrecanases ADAMTS-4 (a disintegrin and metalloproteinase domain with thrombospondin motif) and ADAMTS-5, as well as the tissue inhibitor of metalloproteinase-3. In bovine cartilage explant cultures stimulated with IL-1 to induce aggrecan and collagen degradation over 3 weeks of culture, BMS-345541 was effective in inhibiting the degradation of both aggrecan and collagen. Secreted ADAMTS-4 was not inhibited by BMS-345541 in these explants, whereas ADAMTS-5 secretion was blocked in the same concentration range that inhibited aggrecan degradation. The ability of the IKK inhibitor to block aggrecan and collagen degradation through suppression of metalloproteinase expression, coupled with its ability to block inflammatory cytokine production, shows IKK to be a promising target for the development of novel agents to treat arthritic diseases.

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Crossref · 10.1124/jpet.105.087569

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Authors
Pattoli, M. A., MacMaster, J. F., Gregor, K. R., & Burke, J. R.
Affiliations
Bristol-Myers Squibb (United States) (US)
Venue
The Journal of Pharmacology and Experimental Therapeutics
Publisher
Elsevier BV
Published
2005-10
Volume
315
Issue
1
Pages
382-388
ISSN
0022-3565 (ISSN-L)
OpenAlex
W2142218883
Cited by
56
References
36
Citations by year
2024: 2 · 2022: 3 · 2021: 5 · 2019: 1 · 2018: 4 · 2017: 3 · 2016: 5 · 2015: 1 · 2014: 1 · 2013: 1 · 2012: 3
FWCI
2.64
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
Keywords
BMS-345541, IκB kinase inhibitors, interleukin-1, cartilage degeneration, aggrecan degradation, collagen degradation, matrix metalloproteinases, ADAMTS5, ADAMTS-4, TIMP-3, NF-κB signaling, chondrocytes, cartilage explants, arthritis
MeSH terms
ADAMTS5 Protein, ADAMTS4 Protein, Animals, Cartilage, Cattle, Collagen, Humans, Imidazoles, Interleukin-1, Phosphorylation, Procollagen N-Endopeptidase, Proteoglycans, Quinoxalines, Gene Expression Regulation, Enzymologic, Extracellular Matrix Proteins, Chondrocytes, Lectins, C-Type, Metalloproteases, Protein Kinase Inhibitors, ADAM Proteins, Aggrecans

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