In vitro evaluation of (S)-ibuprofen toxicity on joint cells and explants of cartilage and synovial membrane

Abstract

Intra-articular drug delivery systems (DDSs) are envisaged as interesting alternative to locally release nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen to reduce pain in patients with osteoarthritis. The present study examines the toxicity of (S)-ibuprofen on chondrocytes and synoviocytes isolated from sheep shoulder joint and cultured in monolayers during 72h, and on joint explants (cartilage and capsule) cultured in mono- or in co-culture for 13days. (S)-ibuprofen (5μM up to 1mM) did not reduce the cell viability and protein content when added on chondrocyte monolayers, while at 1mM (S)-ibuprofen reduced (by 8%, p=0.01) the synoviocytes viability compared to untreated cells. During co-culture of joint explants, (S)-ibuprofen at 50μM significantly reduced by 35% the spontaneous release of glycosaminoglycans (GAGs) from cartilage (p=0.0065) whereas in monoculture, (S)-ibuprofen was inactive on GAG metabolism. (S)-ibuprofen at 1mM significantly reduced cell lysis (lactate dehydrogenase leakage) by 74% during monoculture of capsule explants (p=0.0136) and by 35% during co-culture of explants (p=0.0013). Our findings demonstrate that the active isomer of ibuprofen at micro- and millimolar levels was not toxic for chondrocytes and synoviocytes and may reduce at 1mM the cell lysis during culture of joint explants. The limited toxicity of (S)-ibuprofen at low and high concentration in sheep joint shoulder makes this enantiomer a promising drug candidate for the loading of intra-articular DDS.