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Small molecule inhibitors of WNT/?-catenin signaling block IL-1?- and TNF?-induced cartilage degradation.

ABSTRACT: INTRODUCTION: In this study, we tested the ability of small molecule inhibitors of WNT/?-catenin signaling to block interleukin 1? (IL-1?)- and tumor necrosis factor ? (TNF?)-induced cartilage degradation. Proinflammatory cytokines such as IL-1? and TNF? are potent inducers of cartilage degradation by upregulating matrix metalloproteinase (MMP) expression and activity. Because WNT/?-catenin signaling was found to be involved in IL-1?- and TNF?-induced upregulation of MMP activity, we hypothesized that inhibition of WNT/?-catenin signaling might block IL-1?- and TNF?-induced cartilage degradation. We tested the effect of small molecules that block the interaction between ?-catenin and TCF/Lef transcription factors on IL-1?- and TNF?-induced cartilage degradation in mouse fetal metatarsals. METHODS: We used mouse fetal metatarsals treated with IL-1? and TNF? as an ex vivo model for cytokine-induced cartilage degradation. Metatarsals were treated with IL-1? and TNF? in combination with the small molecules PKF115-584, PKF118-310 and CGP049090 at different concentrations and then harvested them for histological and gene expression analysis. RESULTS: We found that IL-1?- and TNF?-induced cartilage degradation in mouse fetal metatarsals was blocked by inhibiting WNT/?-catenin signaling using small molecule PKF115-584 and partially using CGP049090 dose-dependently. In addition, we found that PKF115-584 blocked IL-1?- and TNF?-induced MMP mRNA expression, but did not reverse the inhibitory effect of IL-1? on the expression of cartilage anabolic genes. CONCLUSION: In this study, we show that inhibition of WNT/?-catenin signaling by small molecules can effectively prevent IL-1?- and TNF?-induced cartilage degradation by blocking MMP expression and activity. Furthermore, we elucidate the involvement of WNT/?-catenin signaling in IL-1?- and TNF?-induced cartilage degradation.

SUBMITTER: Landman EB

PROVIDER: S-EPMC3978727 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Small molecule inhibitors of WNT/β-catenin signaling block IL-1β- and TNFα-induced cartilage degradation.

Landman Ellie B M EB Miclea Razvan L RL van Blitterswijk Clemens A CA Karperien Marcel M

Arthritis research & therapy 20130821 4

<h4>Introduction</h4>In this study, we tested the ability of small molecule inhibitors of WNT/β-catenin signaling to block interleukin 1β (IL-1β)- and tumor necrosis factor α (TNFα)-induced cartilage degradation. Proinflammatory cytokines such as IL-1β and TNFα are potent inducers of cartilage degradation by upregulating matrix metalloproteinase (MMP) expression and activity. Because WNT/β-catenin signaling was found to be involved in IL-1β- and TNFα-induced upregulation of MMP activity, we hypo ...[more]

PMID: 23965253

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Project description:Interleukin-1β (IL-1β) is one of the most potent pro-inflammatory cytokines implicated in a wide range of autoinflammatory, autoimmune, infectious, and degenerative diseases. Therefore, many researchers have focused on developing therapeutic molecules that inhibit IL-1β-IL-1 receptor 1 (IL-1R1) interaction for the treatment of IL-1-related diseases. Among IL-1-related diseases, osteoarthritis (OA), is characterized by progressive cartilage destruction, chondrocyte inflammation, and extracellular matrix (ECM) degradation. Tannic acid (TA) has been proposed to have multiple beneficial effects, including anti-inflammatory, anti-oxidant, and anti-tumor activities. However, it is unclear whether TA plays a role in anti-IL-1β activity by blocking IL-1β-IL-1R1 interaction in OA. In this study, we report the anti-IL-1β activity of TA in the progression of OA in both in vitro human OA chondrocytes and in vivo rat OA models. Herein, using-ELISA-based screening, natural compound candidates capable of inhibiting the IL-1β-IL-1R1 interaction were identified. Among selected candidates, TA showed hindering IL-1β-IL-1R1 interaction by direct binding to IL-1β using surface plasmon resonance (SPR) assay. In addition, TA inhibited IL-1β bioactivity in HEK-Blue IL-1-dependent reporter cell line. TA also inhibited IL-1β-induced expression of inducible nitric oxide synthase (NOS2), cyclooxygenase-2 (COX-2), IL-6, tumor necrosis factor-alpha (TNF-α), nitric oxide (NO), and prostaglandin E2 (PGE2) in human OA chondrocytes. Moreover, TA downregulated IL-1β-stimulated matrix metalloproteinase (MMP)3, MMP13, ADAM metallopeptidase with thrombospondin type 1 motif (ADAMTS)4, and ADAMTS5, while upregulating collagen type II (COL2A1) and aggrecan (ACAN). Mechanistically, we confirmed that TA suppressed IL-1β-induced MAPK and NF-κB activation. The protective effects of TA were also observed in a monosodium iodoacetamide (MIA)-induced rat OA model by reducing pain and cartilage degradation and inhibiting IL-1β-mediated inflammation. Collectively, our results provide evidence that TA plays a potential role in OA and IL-1β-related diseases by hindering IL-1β-IL-1R1 interaction and suppressing IL-1β bioactivity.

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Small molecule inhibitors of WNT/?-catenin signaling block IL-1?- and TNF?-induced cartilage degradation.

Publications

Small molecule inhibitors of WNT/β-catenin signaling block IL-1β- and TNFα-induced cartilage degradation.

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