Inhibitory Effects of Pentosan Polysulfate Sodium on MAP-Kinase Pathway and NF-κB Nuclear Translocation in Canine Chondrocytes <i>In Vitro</i>

Abstract

ABSTRACT. Pentosan polysulfate sodium (PPS) has a heparin-like structure and is purificated from the plant of European beech wood. PPS has been used for the treatment of interstitial cystitis for human patients. Recent years, it was newly recognised that PPS reduce pain and inflammation of OA. The molecular biological mechanism of PPS to express its clinical effects is not fully understood. The purpose of the present study is to investigate a mechanism of action of PPS on inflammatory reaction of chondrocytes in vitro. It was evaluated that effects of PPS on interleukin (IL)-1β-induced phosphorylation of mitogen-actiated protein kinases (MAPKs), such as p38, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), nuclear translocation of nuclear factor-kappa B (NF-κB), and matrix metalloproteinase (MMP)-3 production in cultured articular chondrocytes. As a result, in the presence of PPS existence, IL-1β-induced phosphorylation of p38 and ERK were certainly inhibited, while JNK phosphorylation was not affected. Nuclear translocation of NF-κB and MMP-3 production were suppressed by PPS pretreatment prior to IL-1β stimulation. In conclusion, it is strongly suggested that PPS treatment prevents inflammatory intracellular responses induced by IL-1 β through inhibition of phosphorylation of certain MAPKs, p38 and ERK and then nuclear translocation of NF-κB in cultured chondrocytes. These PPS properties may contribute to suppressive consequence of catabolic MMP-3 synthesis. These data might translate the clinical efficacy as PPS treatment could inhibit the cartilage catabolism and related clinical symptoms of OA in dogs. KEY WORD: canine, MAP kinase, NF-κB, osteoarthritis, pentosan polysulfate sodium.doi: 10.1292/jvms.11-0511; J. Vet. Med. Sci. 74(6): 707-711, 2012 In the treatment of canine osteoarthritis (OA), multiple therapeutic intervention tools are used for multimodal pain management, including systemic administration of nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular administration of hyaluronic acid, intravenous or intramuscular administration of disease-modyfying osteoarthritis drugs (DMOADs), the use of oral nutraceutical agents, rehabilitaion and weight management [20]. In particular, DMOADs are most likely to relief pain and other clinical symptoms directly related to joint pathologies [16].It is thought that the pathophysiology of OA is related with the imbalance of reparative and degradation processes leads to loose aggrecans and collagens from extracellular matrix (ECM) of hyaline cartilage, resulted in articular cartilage degeneration [1,15]. As catabolic enzymes of ECM, matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) are playing major role in the process and in establishment of OA pathologies, to which DMOADs should target [19].Pentosan polysulfate sodium (PPS) has a heparin-like structure and is extracted from the plant of European beech wood. In North America and Europe, PPS has been used for several ...

Pentosan polysulfate inhibits IL-1β-induced iNOS, c-Jun and HIF-1α upregulation in canine articular chondrocytes

“…However, NFkB activation which is essential for iNOS induction and p38 lie on two distinct pathways that seem to be independently required for IL-1-induced iNOS expression [9,10]. While our laboratory previously demonstrated the inhibitory effects of PPS on the two pathways [30], by ICC, the present study confirms that indeed PPS impairs IL-1-induced NFkB p65 nuclear translocation but most interestingly we demonstrate that PPS colocalizes with NFkB p65. Therefore, the observed inhibition of IL-1-induced iNOS mRNA upregulation and rcIL-1β + TNF-α + LPS-induced iNOS protein expression by PPS is consistent with the inhibition of the NFkB pathway.…”

“…PPS [30,38–40] and other active glycosaminoglycans (GaGs) [41,42] have been proposed to exert their action through interaction with transcription factors and other intracellular proteins consequently blocking their downstream activity. ICC was performed to investigate colocalization of PPS with NFkB p65 and c-Jun, and to clarify whether PPS could inhibit NFkB p65 and c-Jun nuclear translocation and localization.…”

“…Our laboratory previously showed its involvement in the prevention of inflammatory intracellular responses induced by IL-1β via inhibiting NFkB pathway and the phosphorylation of p38 and ERK but not JNK [30]. However, the JNK pathway has been shown to mediate the activation and transcription of c-Jun, which is required for IL-1-induction of MMP-13 [31].…”

Mesenchymal progenitor cells combined with pentosan polysulfate mediating disc regeneration at the time of microdiscectomy: a preliminary study in an ovine model

“…[77][78][79][80] Pentosan polysulfate has been shown to mediate part of its antiinflammatory effects by downregulating TNF-a activity via the suppression of NF-Kb nuclear translocation and inhibition of the MAPKs pathways. 75,76,85 Since the levels of TNF-a 68 and ADAMTS-4/ADAMTS-5 51 are elevated in degenerative discs and have been implicated in the degradation of disc PGs, the combination of PPS with MPCs in the present study offered several potential advantages over the use of MPCs alone.…”

Systems Based Study of the Therapeutic Potential of Small Charged Molecules for the Inhibition of IL-1 Mediated Cartilage Degradation

“…This interaction may be incorporated into the present model by including competitive interaction between IL-1α and anakinra for the IL-1 receptor. Similarly it has been shown that PPS may exert its principal protective action in cartilage by inhibiting the activity of proteases (aggrecanases and MMPs) and not by binding to IL-1α directly [97, 103]. In this case, the model can be modified to incorporate the PPS dependent activity of aggrecanases and MMPs.…”