Targeting an Imbalance of Inflammatory Factors Induces Regeneration in Osteoarthritic Joints

Researchers here demonstrate that various cell populations found in osteoarthritic joint tissue remain competent and capable of regeneration, but these activities are suppressed by factors found in the local environment. Suspecting an excess of inflammatory signaling as the culprit, the researchers designed an anti-inflammatory cell therapy, employing cell types that act to counter inflammatory signaling. The results were promising in a mouse model of osteoarthritis, and continued to be promising in a small human clinical trial.

It can be hypothesized that functional regeneration of osteochondral defects may occur through the activation of appropriate progenitor cells recruited from the surrounding tissues, such as the synovial membrane, upon the onset of the pro-regenerative phase from the local immune cells. Once these progenitors are activated by trauma, they migrate to the defect site where they attach, proliferate, and undergo chondrogenic differentiation to contribute to tissue regeneration. Subsequently, it can be hypothesized that elements in the synovial environment of osteoarthritis (OA) may interfere with any of these crucial steps, impairing the regenerative potential. These elements would then be a cause, and as a result, a target to treat and potentially cure OA in a clinically effective way.

The synovial fluid (SF) from OA patients was herein identified to be a major inhibitor of the regenerative process in an OA environment. Specifically, the heterogeneous cell population isolated from the SF showed a clear ability to migrate, attach, proliferate, and undergo chondrogenic differentiation, all steps crucial for functional regeneration to occur, under standard assay conditions. However, the presence of autologous SF (aSF) during any of these events drastically impaired these processes. Characterization of the SF cytokine composition linked these results to a specific pro-inflammatory profile, suggesting an imbalance between pro- and anti-inflammatory immune cells in the SF.

On the basis of these findings, an immunomodulatory cell treatment was developed with the goal of restoring joint homeostasis by mimicking crucial events seen during tissue regeneration. The treatment was based on anti-inflammatory cartilage-activated T cells (CATs), which upon coculture with adipose-derived mesenchymal stromal cells (aMSCs), induced chondrogenic priming of the progenitor cells. Intra-articular injection of the final coculture steered articular cartilage regeneration and restored joint homeostasis in a rat OA model. A later clinical evaluation in human patients showed improved quality of life, reduced pain, and articular cartilage regeneration in a compassionate use study.