Failure of cartilage regeneration: emerging hypotheses and related therapeutic strategies

Osteoarthritis (OA) is a disabling condition that affects billions of people worldwide and places a considerable burden on patients and on society owing to its prevalence and economic cost. As cartilage injuries are generally associated with the progressive onset of OA, robustly effective approaches for cartilage regeneration are necessary. Despite extensive research, technical development and clinical experimentation, no current surgery-based, material-based, cell-based or drug-based treatment can reliably restore the structure and function of hyaline cartilage. This paucity of effective treatment is partly caused by a lack of fundamental understanding of why articular cartilage fails to spontaneously regenerate. Thus, research studies that investigate the mechanisms behind the cartilage regeneration processes and the failure of these processes are critical to instruct decisions about patient treatment or to support the development of next-generation therapies for cartilage repair and OA prevention. This Review provides a synoptic and structured analysis of the current hypotheses about failure in cartilage regeneration, and the accompanying therapeutic strategies to overcome these hurdles, including some current or potential approaches to OA therapy. Cartilage defects often fail to heal, which can lead to degenerative changes and ultimately to osteoarthritis. This Review discusses various hypotheses for why articular cartilage fails to regenerate and accompanying potential therapeutic solutions. Key points Multiple pathways can cause cartilage regeneration to fail following injury, thereby leading to a cascade of events that ultimately results in a degenerative disease state. Various hypotheses for why cartilage regeneration fails exist relating to a lack of regeneration-competent cells, pathological mechanical changes, non-resolving inflammation and metabolic switches. Treatment strategies should not only consider the potential mechanisms underlying the initial failure in cartilage regeneration but also the stage of disease progression. The cause of entry into the cascade of events that prevent cartilage regeneration might not necessarily be the target point of exit of an ideal treatment strategy.