Abstract
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. 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. Curcumin induced chondrocyte death in primary cultures (50μM p<0.001and 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). 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]
Curcumin is cytotoxic to primary chondrocytes at 25μm and above Untreated controls retained a mean cell death percentage of less than 1% at 24 hours, 48 hours and five days (Figure 1)
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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