TY - JOUR
T1 - Agrin induces long-term osteochondral regeneration by supporting repair morphogenesis
AU - Eldridge, Suzanne
AU - Barawi, Aida
AU - Wang, Hui
AU - Roelofs, Anke
AU - Kaneva, Magdalena
AU - Guan, Zeyu
AU - Lydon, Helen
AU - Thomas, Bethan L
AU - Thorup, Anne-Sophie
AU - Fernandez Fernandez, Beatriz
AU - Caxaria, Sara
AU - Strachan, Danielle
AU - Ali, Ahmed
AU - Shanmuganathan, Kanatheepan
AU - Pitzalis, Costantino
AU - Whiteford, James
AU - Henson, Frances
AU - McCaskie, Andrew
AU - de Bari, Cosimo
AU - Dell'Accio, Francesco
N1 - Acknowledgments: We thank Prof. F. Luyten and Prof. C. Hartman for the critical reading of this manuscript. The authors thank Technical Staff in the ARM Lab and Staff at the University of Aberdeen’s Animal Facility and Microscopy & Histology Facility for their support.
Funding: We gratefully acknowledge funding support of this work by the MRC (MR/L022893/1, MR/N010973/1, MR/P026362/1), Versus Arthritis (19667, 21515, 20886, 21621), Rosetrees Trust (A1205), the Medical College of St Bartholomew's Hospital Trust and the William Harvey Research Foundation.
PY - 2020/9/2
Y1 - 2020/9/2
N2 - 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.
AB - 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.
KW - AMP RESPONSE ELEMENT
KW - ARTICULAR-CARTILAGE
KW - SYNOVIAL JOINT
KW - GENE-EXPRESSION
KW - STEM-CELLS
KW - TGF-BETA
KW - OSTEOARTHRITIS
KW - PROTEIN
KW - LRP4
KW - MAINTENANCE
UR - http://www.scopus.com/inward/record.url?scp=85090260538&partnerID=8YFLogxK
UR - https://www.repository.cam.ac.uk/handle/1810/311896
U2 - 10.1126/scitranslmed.aax9086
DO - 10.1126/scitranslmed.aax9086
M3 - Article
C2 - 32878982
VL - 12
JO - Science translational medicine
JF - Science translational medicine
SN - 1946-6242
IS - 559
M1 - eaax9086
ER -
