Collagen and aggrecan degradation is blocked in interleukin-1-treated cartilage explants by an inhibitor of IkappaB kinase through suppression of metalloproteinase expression.
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.
Pattoli
Mark A
MA
Immunology, Inflammation, and Pulmonary Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA.
MacMaster
John F
JF
Gregor
Kurt R
KR
Burke
James R
JR
D051722:ADAM Proteins / Q000235:genetics; D000071121:ADAMTS4 Protein; D000071116:ADAMTS5 Protein; D053674:Aggrecans; D000818:Animals; D002356:Cartilage / Q000378:metabolism*; D002417:Cattle; D019902:Chondrocytes / Q000378:metabolism; D003094:Collagen / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D037181:Lectins, C-Type / Q000378:metabolism*; D045726:Metalloproteases / Q000235:genetics*; D010766:Phosphorylation; D011348:Procollagen N-Endopeptidase / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011509:Proteoglycans / Q000378:metabolism*; D011810:Quinoxalines / Q000494:pharmacology
C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; D053674:Aggrecans; D016326:Extracellular Matrix Proteins; D007093:Imidazoles; D007375:Interleukin-1; D037181:Lectins, C-Type; D047428:Protein Kinase Inhibitors; D011509:Proteoglycans; D011810:Quinoxalines; D003094:Collagen; D045726:Metalloproteases; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human; C000603919:Adamts4 protein, mouse