Cartilage breakdown is a feature of osteoarthritis, a leading cause of chronic disability, costing 1.5-2% of the GDP in western countries. There is currently no medicine that halts or reverses cartilage breakdown, resulting in joint instability and pain, therefore this is a priority in medicine. Our previous research indicated that Agrin is a potent chondrogenic factor and is able to enhance cartilage matrix formation. Here we investigate the therapeutic use of Agrin for osteochondral defect repair.
Surgery was performed on skeletally mature mice (wildtype and Gdf5-Cre;Tom reporter mice) and sheep to create critical-sized osteochondral defects; animals were treated with collagen gel supplemented with PBS or collagen gel supplemented with Agrin. In vitro: WNT and CREB reporter assays, chondrogenic assays, transfection, siRNA, qPCR, western blotting & immunocytochemistry. Ex-vivo: histology, microCT and immunohistochemistry.
A single intra-articular administration of Agrin induced long-lasting regeneration of critical-size osteochondral defects in mice, with restoration of tissue architecture and bone-cartilage interface. Agrin attracted joint resident progenitor cells to the site of injury and, through simultaneous activation of CREB and suppression of canonical WNT signalling downstream of β-catenin, induced expression of the chondrogenic stem cell marker GDF5 and differentiation into stable articular chondrocytes, forming stable articular cartilage. In sheep, the Agrin-containing collagen gel resulted in long-lasting regeneration of bone and cartilage, which promoted increased ambulatory activity.
Agrin induces long-term osteochondral regeneration by supporting repair morphogenesis . No ectopic cartilage formation was observed after intra-articular delivery despite the chondrogenic capacity of Agrin. The capacity of Agrin to preserve the architecture of the native tissue is distinct and of important translational relevance. Our findings support the therapeutic use of Agrin for joint surface regeneration.