Agrin induces long-term osteochondral regeneration by supporting repair morphogenesis

Suzanne Eldridge* (Corresponding Author), Aida Barawi, Hui Wang, Anke Roelofs, Magdalena Kaneva, Zeyu Guan, Helen Lydon, Bethan L Thomas, Anne-Sophie Thorup, Beatriz Fernandez Fernandez, Sara Caxaria, Danielle Strachan, Ahmed Ali, Kanatheepan Shanmuganathan, Costantino Pitzalis, James Whiteford, Frances Henson, Andrew McCaskie, Cosimo de Bari, Francesco Dell'Accio

*Corresponding author for this work

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numbereaax9086
Number of pages15
JournalScience translational medicine
Volume12
Issue number559
DOIs
Publication statusPublished - 2 Sep 2020

Keywords

  • AMP RESPONSE ELEMENT
  • ARTICULAR-CARTILAGE
  • SYNOVIAL JOINT
  • GENE-EXPRESSION
  • STEM-CELLS
  • TGF-BETA
  • OSTEOARTHRITIS
  • PROTEIN
  • LRP4
  • MAINTENANCE

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