Cartilage loss leads to osteoarthritis, the most common cause of disability for which there is no cure. Cartilage regeneration, therefore, is a priority in medicine. We report that agrin is a potent chondrogenic factor and that a single intraarticular 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 signaling 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, an agrin-containing collagen gel resulted in long-lasting regeneration of bone and cartilage, which promoted increased ambulatory activity. Our findings support the therapeutic use of agrin for joint surface regeneration.
Agrin induces long-term osteochondral regeneration by supporting repair morphogenesis / Eldridge, S. E.; Barawi, A.; Wang, H.; Roelofs, A. J.; Kaneva, M.; Guan, Z.; Lydon, H.; Thomas, B. L.; Thorup, A. -S.; Fernandez, B. F.; Caxaria, S.; Strachan, D.; Ali, A.; Shanmuganathan, K.; Pitzalis, C.; Whiteford, J. R.; Henson, F.; Mccaskie, A. W.; De Bari, C.; Dell'Accio, F.. - In: SCIENCE TRANSLATIONAL MEDICINE. - ISSN 1946-6234. - 12:559(2020), pp. N/A-N/A. [10.1126/SCITRANSLMED.AAX9086]
Agrin induces long-term osteochondral regeneration by supporting repair morphogenesis
Wang H.;Ali A.;de Bari C.;
2020
Abstract
Cartilage loss leads to osteoarthritis, the most common cause of disability for which there is no cure. Cartilage regeneration, therefore, is a priority in medicine. We report that agrin is a potent chondrogenic factor and that a single intraarticular 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 signaling 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, an agrin-containing collagen gel resulted in long-lasting regeneration of bone and cartilage, which promoted increased ambulatory activity. Our findings support the therapeutic use of agrin for joint surface regeneration.
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