Sorbitol-modified hyaluronic acid reduces oxidative stress, apoptosis and mediators of inflammation and catabolism in human osteoarthritic chondrocytes

Inflamm Res. 2014 Aug;63(8):691-701. doi: 10.1007/s00011-014-0742-4. Epub 2014 May 25.


Objective and design: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aldehydes / metabolism
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacology*
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Apoptosis / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Chondrocytes / drug effects*
  • Chondrocytes / metabolism
  • DNA Fragmentation / drug effects
  • Dinoprostone / metabolism
  • Glutathione Transferase / metabolism
  • Humans
  • Hyaluronic Acid / chemistry
  • Hyaluronic Acid / pharmacology*
  • Hydrogen Peroxide
  • Interleukin-1beta
  • Matrix Metalloproteinase 13 / metabolism
  • Middle Aged
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type II / metabolism
  • Osteoarthritis / metabolism
  • Oxidative Stress / drug effects
  • Reactive Oxygen Species / metabolism
  • Sorbitol / chemistry*


  • Aldehydes
  • Anti-Inflammatory Agents
  • Antioxidants
  • Interleukin-1beta
  • Reactive Oxygen Species
  • Nitric Oxide
  • Sorbitol
  • Hyaluronic Acid
  • Hydrogen Peroxide
  • NOS2 protein, human
  • Nitric Oxide Synthase Type II
  • Glutathione Transferase
  • Matrix Metalloproteinase 13
  • leukotriene-C4 synthase
  • 4-hydroxy-2-nonenal
  • Dinoprostone