Tankyrase inhibition stimulates innate repair capacity in osteoarthritic cartilage

Abstract

Osteoarthritis (OA) is a prevalent degenerative disease, which involves progressive and irreversible destruction of articular cartilage. Despite efforts to regenerate cartilage in osteoarthritic joints, it has been a difficult task as adult cartilage exhibits marginal self-repair capacity. I conducted systems-level factor analysis on mouse reference populations and identified tankyrase as a regulator of the cartilage anabolism axis. Tankyrase inhibition increases the collective expression of cartilage-specific matrix genes in mouse chondrocytes. Moreover, tankyrase inhibition stimulates chondrogenic differentiation of mesenchymal stem cells from mouse limb-bud and human bone marrow. In osteochondral defect model of rats, stem-cell transplantation coupled with tankyrase knockdown results in superior regeneration of cartilage lesions. Mechanistically, the pro-regenerative features of tankyrase inhibition are mainly triggered by regulating SOX9 transcriptional activity. I found that tankyrase binds to and poly(ADP-ribosyl)ates (PARylates) SOX9. Furthermore, in surgically induced OA mouse model, treatment of hydrogel-based tankyrase inhibitor ameliorates OA progression. These results suggest that tankyrase inhibition in treating OA cartilage may be a potential strategy for functional repair of articular cartilage.