Abstract
Objective: Curcumin (diferuloylmethane) is a phytochemical with potent anti-inflammatory and anti-oxidant properties, and has therapeutic potential for the treatment of a range of inflammatory diseases, including osteoarthritis (OA). The aim of this study was to determine whether non-toxic concentrations of curcumin can reduce interleukin-1beta (IL-1β)-stimulated inflammation and catabolism in an explant model of cartilage inflammation. Methods: Articular cartilage explants and primary chondrocytes were obtained from equine metacarpophalangeal joints. Curcumin was added to monolayer cultured primary chondrocytes and cartilage explants in concentrations ranging from 3μM-100μM. Prostaglandin E 2 (PGE 2) and matrix metalloproteinase (MMP)-3 release into the secretome of IL-1β-stimulated explants was measured using a competitive ELISA and western blotting respectively. Proteoglycan (PG) release in the secretome was measured using the 1,9-dimethylmethylene blue (DMMB) assay. Cytotoxicity was assessed with a live/dead assay in monolayer cultures after 24 hours, 48 hours and five days, and in explants after five days. Results: Curcumin induced chondrocyte death in primary cultures (50μM p<0.001 and 100μM p<0.001) after 24 hours. After 48 hours and five days, curcumin (≥25μM) significantly increased cell death ( p<0.001 both time points). In explants, curcumin toxicity was not observed at concentrations up to and including 25μM after five days. Curcumin (≥3μM) significantly reduced IL-1β-stimulated PG ( p<0.05) and PGE 2 release ( p<0.001) from explants, whilst curcumin (≥12μM) significantly reduced MMP-3 release ( p<0.01). Conclusion: Non-cytotoxic concentrations of curcumin exert anti-catabolic and anti-inflammatory effects in cartilage explants.
Highlights
Osteoarthritis (OA) involves destruction of articular cartilage by a combination of mechanical injury, inflammatory mediators and proteolytic enzyme activity[1]
dimethyl sulfoxide (DMSO) controls and the non-steroidal anti-inflammatory drugs (NSAIDs), carprofen, did not significantly increase cell death compared to controls at all time points
This study attempted to address the issue of curcumin cytotoxicity and its anti-inflammatory effects in equine cartilage explants and monolayer chondrocyte cultures
Summary
Osteoarthritis (OA) involves destruction of articular cartilage by a combination of mechanical injury, inflammatory mediators and proteolytic enzyme activity[1]. The high cost and potential negative side effects of conventional pharmacotherapy, i.e. non-steroidal anti-inflammatory drugs (NSAIDs), has stimulated interest in natural plant products with anti-inflammatory properties, as an alternative or adjunct to conventional therapy[2]. These products are being investigated for potential efficacy in a wide range of disorders with an inflammatory component, including arthritis and cancer[3,4]. Published work suggests that curcumin is cytotoxic to both primary chondrocytes[7] and transformed chondrocyte cell lines[8] at 50μM and above. We evaluated the concentrations at which a commercially available curcumin formulation (sourced from Sigma-Aldrich) was cytotoxic to primary equine chondrocytes in both monolayer and explant cultures and determined whether non-toxic concentrations could reduce proteoglycan (PG) loss and inflammatory mediator production in an in vitro model of early OA
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