This open access paper provides a conservative view on the state of research and development of osteoarthritis treatments. Some time is spent on the puzzling nature of inflammation in osteoarthritis, and the failure of immunosuppressive therapies used for other conditions to produce meaningful benefits in this case. Yet senescent cells - and their inflammatory signaling, shown in a number of animal studies to contribute to and even directly cause osteoarthritis - are not mentioned at all. This gives some idea of the mindset in evidence here: lines of research arising in the past five to ten years, and that have not yet progressed to later stage clinical trials, are not worthy of note. The clinical community progresses slowly indeed.
Despite an increasing burden of osteoarthritis in developed societies, target discovery has been slow and there are currently no approved disease-modifying osteoarthritis drugs. This lack of progress is due in part to a series of misconceptions over the years: that osteoarthritis is an inevitable consequence of ageing, that damaged articular cartilage cannot heal itself, and that osteoarthritis is driven by synovial inflammation similar to that seen in rheumatoid arthritis. Recent randomised controlled trials, using treatments repurposed from rheumatoid arthritis, have largely been unsuccessful. Genome-wide studies point to defects in repair pathways, which accords well with recent promise using growth factor therapies or Wnt pathway antagonism.
There are many reasons to be optimistic about new therapeutic developments in osteoarthritis. Although it is true that much of what has been learned in the past few years from clinical studies is what not to use in disease, these negative studies have been highly informative in reminding the medical community that osteoarthritis is distinct from inflammatory arthritidies, such as rheumatoid arthritis. Research has shown that inflammation in osteoarthritis is nuanced and that classical immunomodulatory pathways are not good targets, but that there are several other inflammatory pathways awaiting clinical exploration, including those driven by direct mechanical injury of the cartilage (so-called mechanoflammation), complement, and mast cells.
The nature and role of inflammation in osteoarthritis pathogenesis thus remains unclear. Clarification is crucially important, not only so that we can develop appropriate targeted therapies for patients, but also to decide whether patients require stratification before treatment. There has been a popular move to try to phenotype patients, with a view to personalising their treatment to improve the efficacy of a given drug. However, these phenotypes currently lack cohesion, and here is little or no evidence that stratification by any of these features changes the response to treatment.
Clinical successes point towards a focus on regenerative or anabolic pathways rather than inflammatory ones. This suggestion fits well with preclinical studies, although the reciprocal relationship between repair and inflammation in the chondrocyte suggests that targeting one will probably affect the other. Recent large genome-wide association studies in osteoarthritis also support the concept that osteoarthritis is a failure of repair. Several at-risk loci have been attributed to genes in the TGFβ and FGF pathways, and there is a notable absence of loci that predict the regulation of classical inflammatory genes. Newer targets identified by genome studies, including the retinoic acid pathway, also look promising.