Tissue regeneration in osteoarthritis: the effects of inflammatory cytokines on bioengineering strategies to repair arthritic joints

Osteoarthritis (OA) is the most common form of arthritis worldwide. Historically, treatments for OA have been analgesics, physiotherapy, joint injections and eventually joint replacement surgery. With the advent of tissue engineering (TE), there has been considerable interest in exploiting these techniques to devise new treatments for OA. Despite the development of skeletal stem cell (SSC) constructs aimed at creating viable cartilage and bone, few studies have examined the effects of inflammatory cytokines present in OA synovial tissues, on such constructs. Here, both in vitro and in vivo approaches were used to examine the effects of cytokines on the integrity of such bone constructs.This work confirms IL-1β is a key cytokine for enhancing osteogenic differentiation in OA, whereas TNFα is inhibitory. OA supernatants were obtained from synovial tissue of patients undergoing hip or knee arthroplasty. Most OA supernatants produced an inhibitory effect on osteogenic differentiation in co-cultures with HBMSCs; a minority had additive osteogenic effects, consistent with a more inflammatory subtype of OA. miRNA profiles were analysed for the first time in these co-cultures, producing valuable insights into the pathways through which IL-1β may mediate its effects on osteogenic differentiation. Finally, ex vivo and in vivo models of bone formation, not previously used in the OA field, corroborated the findings of these in vitro studies. These data support the utility of focusing on upregulating IL1-β and inhibiting TNFα to modify existing bone TE strategies being developed locally, for use in the future treatment of OA. Findings were similar with other cell types such as induced pluripotent stem cells, which show promise for future TE strategies. This work also validated the organotypic chick femur and subcutaneous implant models for the future testing of other bioactive factors or miRNAs for incorporation into bone TE approaches for the management of OA