LAUSR

Background Cordycepin (3' deoxyadenosine) is a popular traditional medicine in Asia, taken for conditions associated with ageing. Osteoarthritis (OA) is a common cause of pain and disability in the ageing population. Inflammation is a key component of osteoarthritic pain. Cordycepin is thought to act by inhibiting polyadenylation, the last step of mRNA synthesis, and can potentially have increased therapeutic benefit in OA (anti-inflammatory and analgesic) with fewer side effects than currently available therapies. Objectives The aim of this study was to determine whether cordycepin treatment alters osteoarthritic pain and pathology, and to decipher the mechanisms of action by which cordycepin exerts any potential beneficial actions. Methods OA was induced in male Sprague Dawley rats by intra-articular injection of mono-sodium iodoacetate (MIA; 1mg/50μl) on day 0. Cordycepin was administered orally (2mg/rat mixed in 1g of wet mash) every other day for 2 weeks (pre-emptive study: day 0 to day 14, therapeutic study: day 14 to day 28). Pain behaviour was measured as hind-limb weight-bearing asymmetry and mechanical paw withdrawal thresholds. Joint tissues were collected at days 14 and 28. Joint changes were quantified using histology and immunohistochemistry techniques. Synovial inflammation was quantified as extent of CD68 positive macrophage and cellular infiltration. Synovial angiogenesis was measured as endothelial cells positive for proliferating cell nuclear antigen (PCNA). Safranin-O staining was used to score cartilage damage and bone changes (osteophytes and channels crossing the osteochondral junction [OCJ]). Tartrate-resistant acid phosphatase (TRAP) positive osteoclasts and ADAMTS-5 and MMP13 positive chondrocytes were quantified as additional markers to detect bone and cartilage changes. Results The MIA rodent model of OA pain exhibited significant pain behaviour, synovial inflammation and angiogenesis, cartilage damage, osteophyte formation and subchondral bone changes, compared with non-arthritic controls. A two week pre-emptive and therapeutic treatment with cordycepin reduced MIA-induced pain behaviour and synovial changes (inflammation and angiogenesis). Pre-emptive cordycepin treatment reduced cartilage damage and the level of ADAMTS-5 and MMP13 from the chondrocytes. Pre-emptive and therapeutic cordycepin treatment reduced the number of channels crossing the OCJ and TRAP positive osteoclasts in the subchondral bone, but had no effect on numbers of osteophytes. Therapeutic cordycepin treatment did not alter cartilage damage score or the level of ADAMTS-5 and MMP13 positive chondrocytes. Conclusions Our data show that the analgesic effects of orally administered cordycepin in a pre-emptive and therapeutic protocol are associated with synovial changes (inflammation and angiogenesis) and bone remodelling. Administration of cordycepin before the onset of MIA-induced OA reduced cartilage damage and had a chondroprotective effect. Whereas therapeutically administered cordycepin did not alter cartilage damage. Further studies will investigate whether cordycepin mediated reduction in MIA-induced pathology and pain behaviour is as a result of its direct action on polyadenylation inhibition. Polyadenylation inhibitors could therefore be a novel class of drugs for treating OA. Disclosure of Interest None declared