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

Pentosan polysulfate inhibits IL-1β-induced iNOS, c-Jun and HIF-1α upregulation in canine articular chondrocytes - Download this document for free, or read online. Document in PDF available to download.

Osteoarthritic OA chondrocytes are shown to express inducible nitric oxide synthase iNOS which produces high concentrations of nitric oxide NO, particularly when stimulated with proinflammatory cytokines. NO is involved in OA cartilage degradation. On the other hand, c-Jun N-terminal Kinase JNK pathway mediates the activation and transcription of c-Jun, which is required for interleukin-1 IL-1-induction of matrix metalloproteinases-13 MMP-13 in OA pathogenesis. Therefore, the selective inhibition of iNOS and c-Jun is a promising target for treatment and prevention of OA. The purpose of the study was to investigate the inhibitory effects of pentosan polysulfate PPS on IL-1β-induced iNOS, c-Jun and HIF-α isoforms upregulation in canine articular chondrocytes CACs. Primary P0 chondrocytes were isolated and cultured from femoral head cartilages of three 3 dogs. First passage P1 chondrocytes were preincubated with 0, 1, 5, 15 and 40 μg-mL of PPS for 4 hr before treatment with 10 ng-mL rhIL-1β for a further 8 hr. In addition, we evaluated the effects of single and multiple cytokine with or without LPS on iNOS protein induction. PPS significantly inhibited P < 0.05 IL-1β-induced iNOS, c-Jun and HIF-1α mRNA upregulation in a dose-dependent pattern. iNOS mRNA was significantly inhibited at 15 and 40 μg-mL whereas c-Jun and HIF-1α were significantly downregulated at 5, 15 and 40 μg-mL of PPS compared to chondrocytes treated with only rhIL-1β. Intriguingly, CACs were recalcitrant to single IL-1β, TNF-α or LPS-induction of iNOS protein including to a combination of IL-1β+TNF-α, IL-1β+LPS except to TNF-α+LPS and IL-1β+TNF-α+LPS suggestive of a protective mechanism from iNOS detrimental effects on perpetuating OA. IL-1β+TNF-α+LPS-induced iNOS protein expression was significantly abrogated by PPS. We demonstrate for the first time that PPS is a novel inhibitor of IL-1β-induced iNOS, c-Jun, and HIF-1α mRNA upregulation and iNOS protein induction which may be beneficial for prevention and treatment OA.

Author: Eugene C. Bwalya , Sangho Kim, Jing Fang, H. M. Suranji Wijekoon, Kenji Hosoya, Masahiro Okumura



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