Inhibition of inflammation by pentosan polysulfate impedes the development and progression of severe diabetic nephropathy in aging C57B6 mice

Wu, Jin; Guan, Tian Jun; Zheng, Shirong; Grosjean, Fabrizio; Liu, Weicheng; Xiong, Huabao; Gordon, Ronald E.; Vlassara, Helen; Striker, Gary E.; Zhao, Feng

doi:10.1038/labinvest.2011.93

Cited by 51 publications

(65 citation statements)

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“…In diabetic kidney nephropathy, disease pathogenesis is dependent on the cellular infiltration of macrophages and proinflammatory and chemoattractant factors similar to those associated with alphavirus arthritis. These include CCL-2, RANTES, CXCL1, and tumor necrosis factor alpha (TNF-␣) (29,41). Our data are consistent with those observed for PPS treatment in diabetic nephropathy, where it reduced the macrophage infiltration and suppressed the induction of proinflammatory factors (41).…”

Section: Table 2 Long-term Pps Treatment Decreases the Expression Of supporting

confidence: 89%

Pentosan Polysulfate: a Novel Glycosaminoglycan-Like Molecule for Effective Treatment of Alphavirus-Induced Cartilage Destruction and Inflammatory Disease

Herrero

Foo

Sheng

et al. 2015

J Virol

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Arthritogenic alphaviruses such as Ross River virus (RRV) and chikungunya virus (CHIKV) cause large-scale epidemics of severe musculoskeletal disease and have been progressively expanding their global distribution. Since its introduction in July 2014, CHIKV now circulates in the United States. The hallmark of alphavirus disease is crippling pain and inflammation of the joints, a similar immunopathology to rheumatoid arthritis. The use of glycans as novel therapeutics is an area of research that has increased in recent years. Here, we describe the promising therapeutic potential of the glycosaminoglycan (GAG)-like molecule pentosan polysulfate (PPS) to alleviate virus-induced arthritis. Mouse models of RRV and CHIKV disease were used to characterize the extent of cartilage damage in infection and investigate the potential of PPS to treat disease. This was assessed using histological analysis, real-time PCR, and fluorescence-activated cell sorting (FACS). Alphaviral infection resulted in cartilage destruction, the severity of which was alleviated by PPS therapy during RRV and CHIKV clinical disease. The reduction in cartilage damage corresponded with a significant reduction in immune infiltrates. Using multiplex bead arrays, PPS treatment was found to have significantly increased the anti-inflammatory cytokine interleukin-10 and reduced proinflammatory cytokines, typically correlated with disease severity. Furthermore, we reveal that the severe RRV-induced joint pathology, including thinning of articular cartilage and loss of proteoglycans in the cartilage matrix, was diminished with treatment. PPS is a promising new therapy for alphavirus-induced arthritis, acting to preserve the cartilage matrix, which is damaged during alphavirus infection. Overall, the data demonstrate the potential of glycotherapeutics as a new class of treatment for infectious arthritis. IMPORTANCEThe hallmark of alphavirus disease is crippling pain and joint arthritis, which often has an extended duration. In the past year, CHIKV has expanded into the Americas, with approximately 1 million cases reported to date, whereas RRV continues to circulate in the South Pacific. Currently, there is no licensed specific treatment for alphavirus disease, and the increasing spread of infection highlights an urgent need for therapeutic intervention strategies. Pentosan polysulfate (PPS) is a glycan derivative that is orally bioavailable, has few toxic side effects, and is currently licensed under the name Elmiron for the treatment of cystitis in the United States. Our findings show that RRV infection damages the articular cartilage, including a loss of proteoglycans within the joint. Furthermore, treatment with PPS reduced the severity of both RRV-and CHIKV-induced musculoskeletal disease, including a reduction in inflammation and joint swelling, suggesting that PPS is a promising candidate for drug repurposing for the treatment of alphavirus-induced arthritis.A rthropod-borne arthritogenic alphaviruses such as Ross River virus (RRV) and chikungu...

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Section: Table 2 Long-term Pps Treatment Decreases the Expression Of supporting

confidence: 89%

Pentosan Polysulfate: a Novel Glycosaminoglycan-Like Molecule for Effective Treatment of Alphavirus-Induced Cartilage Destruction and Inflammatory Disease

Herrero

Foo

Sheng

et al. 2015

J Virol

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“…Moreover, since our study is based on only in vitro, it is necessary to consider a real reaction in vivo study. However, previous reports showed the inhibitory effect of PPS on TNF-α induced NF-κB activation in vivo [23], supporting the PPS efficacy in vitro.…”

Section: Discussionmentioning

confidence: 62%

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

Sunaga

Hosoya

et al. 2012

The Journal of Veterinary Medical Science

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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 ...

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“…[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.…”

Section: Discussionmentioning

confidence: 98%

“…26 Pentosan polysulfate is approved for the treatment of interstitial cystitis in the US, 3 but it is also an anti-osteoarthritic drug. 23,24,43 Apart from its antiinflammatory properties, 8,9,40,41,71,72,85 PPS is a potent leukocyte elastase 4 and aggrecanase (ADAMTS-4 and ADAMTS-5) inhibitor. [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.…”

Section: Discussionmentioning

confidence: 99%

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

Oehme

Ghosh

Shimmon

et al. 2014

SPI

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Object Following microdiscectomy, discs generally fail to undergo spontaneous regeneration and patients may experience chronic low-back pain and recurrent disc prolapse. In published studies, formulations of mesenchymal progenitor cells combined with pentosan polysulfate (MPCs+PPS) have been shown to regenerate disc tissue in animal models, suggesting that this approach may provide a useful adjunct to microdiscectomy. The goal of this preclinical laboratory study was to determine if the transplantation of MPCs+PPS, embedded in a gelatin/fibrin scaffold (SCAF), and transplanted into a defect created by microdiscectomy, could promote disc regeneration. Methods A standardized microdiscectomy procedure was performed in 18 ovine lumbar discs. The subsequent disc defects were randomized to receive either no treatment (NIL), SCAF only, or the MPC+PPS formulation added to SCAF (MPCs+PPS+SCAF). Necropsies were undertaken 6 months postoperatively and the spines analyzed radiologically (radiography and MRI), biochemically, and histologically. Results No adverse events occurred throughout the duration of the study. The MPC+PPS+SCAF group had significantly less reduction in disc height compared with SCAF-only and NIL groups (p < 0.05 and p < 0.01, respectively). Magnetic resonance imaging Pfirrmann scores in the MPC+PPS+SCAF group were significantly lower than those in the SCAF group (p = 0.0213). The chaotropic solvent extractability of proteoglycans from the nucleus pulposus of MPC+PPS+SCAF-treated discs was significantly higher than that from the SCAF-only discs (p = 0.0312), and using gel exclusion chromatography, extracts from MPC+PPS+SCAF-treated discs also contained a higher percentage of proteoglycan aggregates than the extracts from both other groups. Analysis of the histological sections showed that 66% (p > 0.05) of the MPC+PPS+SCAF-treated discs exhibited less degeneration than the NIL or SCAF discs. Conclusions These findings demonstrate the capacity of MPCs in combination with PPS, when embedded in a gelatin sponge and sealed with fibrin glue in a microdiscectomy defect, to restore disc height, disc morphology, and nucleus pulposus proteoglycan content.

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Inhibition of inflammation by pentosan polysulfate impedes the development and progression of severe diabetic nephropathy in aging C57B6 mice

Cited by 51 publications

References 50 publications

Pentosan Polysulfate: a Novel Glycosaminoglycan-Like Molecule for Effective Treatment of Alphavirus-Induced Cartilage Destruction and Inflammatory Disease

Pentosan Polysulfate: a Novel Glycosaminoglycan-Like Molecule for Effective Treatment of Alphavirus-Induced Cartilage Destruction and Inflammatory Disease

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

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

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