IGF-1 and PDGF-bb Suppress IL-1 beta-Induced Cartilage Degradation through Down-Regulation of NF-kappa B Signaling: Involvement of Src/PI-3K/AKT Pathway

Abstract

Objective: Interleukin-1 beta (IL-1 beta) is a pro-inflammatory cytokine that plays a key role in the pathogenesis of osteoarthritis (OA). Growth factors (GFs) capable of antagonizing the catabolic actions of cytokines may have therapeutic potential in the treatment of OA. Herein, we investigated the potential synergistic effects of insulin-like growth factor (IGF-1) and platelet-derived growth factor (PDGF-bb) on different mechanisms participating in IL-1 beta-induced activation of nuclear transcription factor-kappa B (NF-kappa B) and apoptosis in chondrocytes. Methods: Primary chondrocytes were treated with IL-1 beta to induce dedifferentiation and co-treated with either IGF-1 or/and PDGF-bb and evaluated by immunoblotting and electron microscopy. Results: Pretreatment of chondrocytes with IGF-1 or/and PDGF-bb suppressed IL-1b-induced NF-kappa B activation via inhibition of IkB-alpha kinase. Inhibition of IkB-alpha kinase by GFs led to the suppression of IkB-alpha phosphorylation and degradation, p65 nuclear translocation and NF-kappa B-regulated gene products involved in inflammation and cartilage degradation (COX-2, MMPs) and apoptosis (caspase-3). GFs or BMS-345541 (specific inhibitor of the IKK) reversed the IL-1 beta-induced down-regulation of collagen type II, cartilage specific proteoglycans, beta 1-integrin, Shc, activated MAPKinase, Sox-9 and up-regulation of active caspase-3. Furthermore, the inhibitory effects of IGF-1 or/and PDGF-bb on IL-1 beta-induced NF-kappa B activation were sensitive to inhibitors of Src (PP1), PI-3K (wortmannin) and Akt (SH-5), suggesting that the pathway consisting of non-receptor tyrosine kinase (Src), phosphatidylinositol 3-kinase and protein kinase B must be involved in IL-1 beta signaling. Conclusion: The results presented suggest that IGF-1 and PDGF-bb are potent inhibitors of IL-1 beta-mediated activation of NF kappa B and apoptosis in chondrocytes, may be mediated in part through suppression of Src/PI-3K/AKT pathway, which may contribute to their anti-inflammatory effects.