IL-1 in osteoarthritis: time for a critical review of the literature

The concept of interleukin-1 (IL-1) as a target in osteoarthritis (OA) has been an attractive one for many years. It is a highly potent inducer of cartilage degradation, causing the induction of mRNA and controlling the bioavailability of disease-relevant proteases such as ADAMTS5 and MMP13. It drives synovitis and can induce other disease-relevant genes such as nerve growth factor, a key pain sensitiser in OA. However, the quality of evidence for its involvement in disease is modest. Descriptive studies have demonstrated expression of IL-1α and β in OA cartilage and elevated levels in the synovial fluid of some patients. Agnostic transcriptomic and genomic analyses do not identify IL-1 as a key pathway. In vivo models show a conflicting role for this molecule; early studies using therapeutic approaches in large animal models show a benefit, but most murine studies fail to demonstrate protection where the ligands (IL-1α/β), the cytokine activator (IL-1-converting enzyme), or the receptor (IL-1R) have been knocked out. Recently, a number of large double-blind randomised controlled clinical studies targeting IL-1 have failed. Enthusiasm for IL-1 as a target in OA is rapidly dwindling.