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Matrix-Bound Growth Factors are Released upon Cartilage Compression by an Aggrecan-Dependent Sodium Flux that is Lost in Osteoarthritis

View ORCID ProfileStuart J. Keppie, Jessica C. Mansfield, Xiaodi Tang, Christopher J. Philp, Helen K. Graham, Patrik Önnerfjord, Alanna Wall, Celia McLean, C. Peter Winlove, Michael J. Sherratt, Galina E. Pavlovskaya, View ORCID ProfileTonia L Vincent
doi: https://doi.org/10.1101/2021.01.31.428791
Stuart J. Keppie
aKennedy Institute of Rheumatology, University of Oxford, Oxford, OX3 7FY
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  • ORCID record for Stuart J. Keppie
Jessica C. Mansfield
bSchool of Physics and Astronomy, University of Exeter, Exeter, EX4 4QL
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Xiaodi Tang
aKennedy Institute of Rheumatology, University of Oxford, Oxford, OX3 7FY
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Christopher J. Philp
cSir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, NG7 2QX
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Helen K. Graham
dSchool of Biological Sciences, The University of Manchester, Manchester, M13 9PT
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Patrik Önnerfjord
eRheumatology and Molecular Skeletal Biology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
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Alanna Wall
aKennedy Institute of Rheumatology, University of Oxford, Oxford, OX3 7FY
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Celia McLean
aKennedy Institute of Rheumatology, University of Oxford, Oxford, OX3 7FY
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C. Peter Winlove
bSchool of Physics and Astronomy, University of Exeter, Exeter, EX4 4QL
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Michael J. Sherratt
dSchool of Biological Sciences, The University of Manchester, Manchester, M13 9PT
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Galina E. Pavlovskaya
cSir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, NG7 2QX
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Tonia L Vincent
aKennedy Institute of Rheumatology, University of Oxford, Oxford, OX3 7FY
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  • ORCID record for Tonia L Vincent
  • For correspondence: Tonia.Vincent@Kennedy.ox.ac.uk
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Abstract

Articular cartilage is a dense extracellular matrix-rich tissue that degrades following chronic mechanical stress, resulting in osteoarthritis (OA). The tissue has low intrinsic repair especially in aged and osteoarthritic joints. Here we describe three pro-regenerative factors; fibroblast growth factor 2 (FGF2), connective tissue growth factor, bound to transforming growth factor-beta (CTGF-TGFβ), and hepatoma-derived growth factor (HDGF), that are rapidly released from the pericellular matrix (PCM) of articular cartilage upon mechanical injury. All three growth factors bound heparan sulfate, and were displaced by exogenous NaCl. We hypothesised that sodium, sequestered within the aggrecan-rich matrix, was freed by injurious compression, thereby enhancing the bioavailability of pericellular growth factors. Indeed, growth factor release was abrogated when cartilage aggrecan was depleted by IL-1 treatment, and in severely damaged human osteoarthritic cartilage. A flux in free matrix sodium upon mechanical compression of cartilage was visualised by 23Na magnetic resonance imaging (MRI) just below the articular surface. This corresponded to a region of reduced tissue stiffness, measured by scanning acoustic microscopy and second harmonic generation microscopy, and where Smad2/3 was phosphorylated upon cyclic compression. Our results describe a novel intrinsic repair mechanism, controlled by matrix stiffness and mediated by the free sodium concentration, in which heparan sulfate-bound growth factors are released from cartilage upon injurious load. They identify aggrecan as a depot for sequestered sodium, explaining why osteoarthritic tissue loses its ability to repair. Treatments that restore matrix sodium to allow appropriate release of growth factors upon load are predicted to enable intrinsic cartilage repair in osteoarthritis.

Significance Statement Osteoarthritis is the most prevalent musculoskeletal disease, affecting 250 million people worldwide 1. We identify a novel intrinsic repair response in cartilage, mediated by aggrecan-dependent sodium flux, and dependent upon matrix stiffness, which results in the release of a cocktail of pro-regenerative growth factors after injury. Loss of aggrecan in late-stage osteoarthritis prevents growth factor release and likely contributes to disease progression. Treatments that restore matrix sodium in osteoarthritis may recover the intrinsic repair response to improve disease outcome.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • http://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD023890

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Matrix-Bound Growth Factors are Released upon Cartilage Compression by an Aggrecan-Dependent Sodium Flux that is Lost in Osteoarthritis
Stuart J. Keppie, Jessica C. Mansfield, Xiaodi Tang, Christopher J. Philp, Helen K. Graham, Patrik Önnerfjord, Alanna Wall, Celia McLean, C. Peter Winlove, Michael J. Sherratt, Galina E. Pavlovskaya, Tonia L Vincent
bioRxiv 2021.01.31.428791; doi: https://doi.org/10.1101/2021.01.31.428791
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Matrix-Bound Growth Factors are Released upon Cartilage Compression by an Aggrecan-Dependent Sodium Flux that is Lost in Osteoarthritis
Stuart J. Keppie, Jessica C. Mansfield, Xiaodi Tang, Christopher J. Philp, Helen K. Graham, Patrik Önnerfjord, Alanna Wall, Celia McLean, C. Peter Winlove, Michael J. Sherratt, Galina E. Pavlovskaya, Tonia L Vincent
bioRxiv 2021.01.31.428791; doi: https://doi.org/10.1101/2021.01.31.428791

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