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.