title: Sorbitol-modified hyaluronic acid reduces oxidative stress, apoptosis and mediators of inflammation and catabolism in human osteoarthritic chondrocytes.
abstract: OBJECTIVE
  Our study was designed to elucidate the precise molecular mechanisms by which sorbitol-modified hyaluronic acid (HA/sorbitol) exerts beneficial effects in osteoarthritis (OA).
  
  
  METHODS
  Human OA chondrocytes were treated with increasing doses of HA/sorbitol ± anti-CD44 antibody or with sorbitol alone and thereafter with or without interleukin-1beta (IL-1β) or hydrogen peroxide (H2O2). Signal transduction pathways and parameters related to oxidative stress, apoptosis, inflammation, and catabolism were investigated.
  
  
  RESULTS
  HA/sorbitol prevented IL-1β-induced oxidative stress, as measured by reactive oxygen species, p47-NADPH oxidase phosphorylation, 4-hydroxynonenal (HNE) production and HNE-metabolizing glutathione-S-transferase A4-4 expression. Moreover, HA/sorbitol stifled IL-1β-induced metalloproteinase-13, nitric oxide (NO) and prostaglandin E2 release as well as inducible NO synthase expression. Study of the apoptosis process revealed that this gel significantly attenuated cell death, caspase-3 activation and DNA fragmentation elicited by exposure to a cytotoxic H2O2 dose. Examination of signaling pathway components disclosed that HA/sorbitol prevented IL-1β-induced p38 mitogen-activated protein kinase and nuclear factor-kappa B activation, but not that of extracellular signal-regulated kinases 1 and 2. Interestingly, the antioxidant as well as the anti-inflammatory and anti-catabolic effects of HA/sorbitol were attributed to sorbitol and HA, respectively.
  
  
  CONCLUSIONS
  Altogether, our findings support a beneficial effect of HA/sorbitol in OA through the restoration of redox status and reduction of apoptosis, inflammation and catabolism involved in cartilage damage.
authors.affiliation: Orthopaedics Research Laboratory, Hôpital du Sacré-Cœur de Montréal, Room K-3045, 5400 Gouin Blvd. West, Montreal, QC, H4J 1C5, Canada.
authors.forename: John-Max
authors.initials: JM
authors.lastname: Mongkhon
authors.forename: Maryane
authors.initials: M
authors.lastname: Thach
authors.forename: Qin
authors.initials: Q
authors.lastname: Shi
authors.forename: Julio C
authors.initials: JC
authors.lastname: Fernandes
authors.forename: Hassan
authors.initials: H
authors.lastname: Fahmi
authors.forename: Mohamed
authors.initials: M
authors.lastname: Benderdour
mesh_terms: D000368:Aged; D000447:Aldehydes / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D015232:Dinoprostone / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry / Q000494:pharmacology*; D006861:Hydrogen Peroxide; D053583:Interleukin-1beta; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010003:Osteoarthritis / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013012:Sorbitol / Q000737:chemistry*
chemical_list: D000447:Aldehydes; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D053583:Interleukin-1beta; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D013012:Sorbitol; D006820:Hyaluronic Acid; D006861:Hydrogen Peroxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D005982:Glutathione Transferase; D053509:Matrix Metalloproteinase 13; C041116:leukotriene-C4 synthase; C027576:4-hydroxy-2-nonenal; D015232:Dinoprostone