Signal transduction pathways involving p38 MAPK, JNK, NFkappaB and AP-1 influences the response of chondrocytes cultured in agarose constructs to IL-1beta and dynamic compression.

OBJECTIVE AND DESIGN:To examine whether inhibitors of the MAPK pathways will influence the response of bovine chondrocytes cultured in agarose constructs to IL-1beta and dynamic compression. METHODS:Dose-response studies were conducted under IL-1beta conditions with either SB203580, SP600125, PDTC or curcumin. In separate experiments, constructs were treated with IL-1beta and an appropriate concentration of inhibitor and subjected to 15% dynamic compression. Nitrite and PGE2 release, 35SO4 and [3H]-thymidine incorporation were subsequently measured using biochemical assays. RESULTS:All inhibitors reduced the IL-1beta induced nitrite and PGE2 release in a dose-dependent manner. The inhibition of [3H]-thymidine incorporation by IL-1beta was partially reversed with SB203580, SP600125 or curcumin, but not PDTC. In most cases, the inhibitors reduced 35SO4 incorporation with IL-1beta. For the mechanical loading studies, the inhibitors reduced the compression-induced inhibition of nitrite and PGE2 release and restored [3H]-thymidine and 35SO4 incorporation. CONCLUSIONS:The MAPK, AP-1 and NF-kappaB signalling pathways are involved in the upregulation of NO and PGE2 release by IL-1beta. Dynamic compression stimulates cell proliferation and proteoglycan synthesis in the presence of IL-1beta and/or inhibitors of the MAPKs and NFkappaB and AP-1 signalling pathways. This experimental approach could provide valuable information for the biophysical/pharmacological treatment of OA.

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