Modulating soluble mediators to restore joint homeostasis

Regenerative therapy meets a previously unmet medical need in current clinical care. Autologous chondrocye implantation results in significantly better clinical outcome than microfracture in patients with defects > 4 cm2 at two years follow-up. This information is of great value for the evidence-based, selective indication of ACI. In addition to the need to select patients most likely to benefit from cell-based therapies, there still is an unmet medical need to improve this treatment. The synovial fluid of patients with symptomatic cartilage defects and OA are each characterized by a distinct profile of soluble mediators, in which several pro-inflammatory but also pro-repair cytokines are elevated compared to donors without joint pathology that may both affect cartilage regeneration. Despite the increased presence of inflammatory mediators, inhibition of individual inflammatory mediators or enzymes did not have large effects on cartilage regeneration, possibly due to counteracting factors. It is therefore not easy to identify which factors are contributing most to the effects on cartilage regeneration. In order to improve cell-based regenerative therapies, modulation of at least several soluble mediators will likely be needed. We here describe chondrocytes to be potent producers of cytokines that, in addition to the other tissues of the knee joint, contribute greatly to the presence of these soluble factors in the synovial fluid. Additionally, local concentrations of cytokines in cartilage tissue were sometimes many times higher than in a similar volume of synovial fluid. Therefore, locally acting soluble mediators may be very different from those in the synovial fluid and affect chondrocytes in an auto- or paracrine manner. To improve the quality of repair tissue and clinical outcome, an integrative approach addressing multiple soluble mediators, not limited to those present in the synovial fluid but also targeting endogenous production by chondrocytes and addressing the chondrocyte micro-environment will be necessary.