Agrin induces long-term osteochondral regeneration by supporting repair morphogenesis

Suzanne  Eldridge; 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

doi:10.1126/scitranslmed.aax9086

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 journal › Article › peer-review

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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 language	English
Article number	eaax9086
Number of pages	15
Journal	Science translational medicine
Volume	12
Issue number	559
DOIs	https://doi.org/10.1126/scitranslmed.aax9086
Publication status	Published - 2 Sept 2020

Bibliographical note

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.

Keywords

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

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Bari_et_al_STM_AgrinInducesLong_AAM
This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in ScienceTranslational Medicine on Vol. 12, Issue 559 and 02 Sept 2020, DOI: http://doi.org/10.1126/scitranslmed.aax9086
Accepted author manuscript, 2.85 MBLicence: Unspecified

Cite this

Eldridge, S., Barawi, A., Wang, H., Roelofs, A., Kaneva, M., Guan, Z., Lydon, H., Thomas, B. L., Thorup, A.-S., Fernandez Fernandez, B., Caxaria, S., Strachan, D., Ali, A., Shanmuganathan, K., Pitzalis, C., Whiteford, J., Henson, F., McCaskie, A., de Bari, C., & Dell'Accio, F. (2020). Agrin induces long-term osteochondral regeneration by supporting repair morphogenesis. Science translational medicine, 12(559), Article eaax9086. https://doi.org/10.1126/scitranslmed.aax9086

Eldridge, S, Barawi, A, Wang, H, Roelofs, A, Kaneva, M, Guan, Z, Lydon, H, Thomas, BL, Thorup, A-S, Fernandez Fernandez, B, Caxaria, S, Strachan, D, Ali, A, Shanmuganathan, K, Pitzalis, C, Whiteford, J, Henson, F, McCaskie, A, de Bari, C & Dell'Accio, F 2020, 'Agrin induces long-term osteochondral regeneration by supporting repair morphogenesis', Science translational medicine, vol. 12, no. 559, eaax9086. https://doi.org/10.1126/scitranslmed.aax9086

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title = "Agrin induces long-term osteochondral regeneration by supporting repair morphogenesis",

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

note = "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{\textquoteright}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. ",

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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

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UR - https://www.repository.cam.ac.uk/handle/1810/311896

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DO - 10.1126/scitranslmed.aax9086

M3 - Article

C2 - 32878982

SN - 1946-6242

VL - 12

JO - Science translational medicine

JF - Science translational medicine

IS - 559

M1 - eaax9086

ER -

Agrin induces long-term osteochondral regeneration by supporting repair morphogenesis

Abstract

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Anke Roelofs

Microscopy and Histology

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Agrin induces long-term osteochondral regeneration by supporting repair morphogenesis

Abstract

Bibliographical note

Keywords

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Profiles

Anke Roelofs

Equipment

Microscopy and Histology

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