Effects of flavonoids on matrix metalloproteinase-13 expression of interleukin-1β-treated articular chondrocytes and their cellular mechanisms: Inhibition of c-Fos/AP-1 and JAK/STAT signaling pathways

Abstract

To identify the therapeutic potential for cartilage degradation and its action mechanisms, the effects of naturally-occurring flavonoids on matrix metalloproteinase-13 (MMP-13) induction were examined in the human chondrocyte cell line SW1353. Flavones including apigenin and wogonin strongly inhibited MMP-13 induction in interleukin (IL)-1β-treated SW1353 cells, while flavonols such as kaempferol, quercetin, and flavanone (naringenin) did not at 5 - 25 μM. Apigenin and wogonin primarily inhibit MMP-13 by blocking the c-Fos / activator protein-1 (AP-1) and Janus kinase 2 (JAK2) / signal transducer and activator of transcription 1/2 (STAT1/2) pathways, but not nuclear factor-κB (NF-κB) signaling. Apigenin was also shown to inhibit extracellular matrix degradation in rabbit cartilage culture. The following study using some synthetic flavones demonstrated that A-ring C-5,7-dihydroxyl and B-ring dihydroxyl substitution at C-2,3, C-2,4, or C-3,4 are important for the suppression of MMP-13 expression. Among these flavones, 2?,3?,5,7- tetrahydroxyflavone also inhibited both the c-Fos/AP-1 and STAT1/2 pathways. Taken together, these results indicate that certain flavonoids, especially flavones, inhibit MMP-13 expression in IL-1β-treated chondrocytes, at least in part, by suppressing the c-Fos/AP-1 and JAK2/STAT1/2 pathways. Furthermore, these findings suggest that some flavonoids have the potential for protecting against collagen matrix breakdown in the cartilage of diseased tissues such as those found in arthritic disorders. © The Japanese Pharmacological Society.