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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-TGF\u03b2), 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 -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 OA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance Statement<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/function\/zqab037","type":"journal-article","created":{"date-parts":[[2021,8,2]],"date-time":"2021-08-02T11:58:11Z","timestamp":1627905491000},"source":"Crossref","is-referenced-by-count":26,"title":["Matrix-Bound Growth Factors are Released upon Cartilage Compression by an Aggrecan-Dependent Sodium Flux that is Lost in Osteoarthritis"],"prefix":"10.1152","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2069-544X","authenticated-orcid":false,"given":"Stuart J","family":"Keppie","sequence":"first","affiliation":[{"name":"Kennedy Institute of Rheumatology, University of Oxford, Oxford, OX3 7FY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica C","family":"Mansfield","sequence":"additional","affiliation":[{"name":"School of Physics and Astronomy, University of Exeter, Exeter, EX4 4QL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodi","family":"Tang","sequence":"additional","affiliation":[{"name":"Kennedy Institute of Rheumatology, University of Oxford, Oxford, OX3 7FY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J","family":"Philp","sequence":"additional","affiliation":[{"name":"Sir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, NG7 2QX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen K","family":"Graham","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, The University of Manchester, Manchester, M13 9PT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrik","family":"\u00d6nnerfjord","sequence":"additional","affiliation":[{"name":"Rheumatology and Molecular Skeletal Biology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alanna","family":"Wall","sequence":"additional","affiliation":[{"name":"Kennedy Institute of Rheumatology, University of Oxford, Oxford, OX3 7FY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia","family":"McLean","sequence":"additional","affiliation":[{"name":"Kennedy Institute of Rheumatology, University of Oxford, Oxford, OX3 7FY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C Peter","family":"Winlove","sequence":"additional","affiliation":[{"name":"School of Physics and Astronomy, University of Exeter, Exeter, EX4 4QL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J","family":"Sherratt","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, The University of Manchester, Manchester, M13 9PT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galina E","family":"Pavlovskaya","sequence":"additional","affiliation":[{"name":"Sir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, NG7 2QX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tonia L","family":"Vincent","sequence":"additional","affiliation":[{"name":"Kennedy Institute of Rheumatology, University of Oxford, Oxford, OX3 7FY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","published-online":{"date-parts":[[2021,8,2]]},"reference":[{"issue":"10159","key":"2021122118060061700_bib1","first-page":"1789","article-title":"Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990\u20132017: a systematic analysis for the global burden of disease study 2017","volume":"392","author":"GBD 2017 Disease and Injury Incidence and Prevalence Collaborators","year":"2018","journal-title":"Lancet North Am Ed"},{"issue":"1","key":"2021122118060061700_bib2","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/sj.cr.7290106","article-title":"Structure and function of aggrecan","volume":"12","author":"Kiani","year":"2002","journal-title":"Cell Res"},{"issue":"7","key":"2021122118060061700_bib3","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1016\/j.joca.2007.01.021","article-title":"FGF-2 is bound to perlecan in the pericellular matrix of articular cartilage, where it acts as a chondrocyte mechanotransducer","volume":"15","author":"Vincent","year":"2007","journal-title":"Osteoarth Cartil"},{"issue":"10182","key":"2021122118060061700_bib4","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1016\/S0140-6736(19)30417-9","article-title":"Osteoarthritis","volume":"393","author":"Hunter","year":"2019","journal-title":"Lancet North Am Ed"},{"issue":"3","key":"2021122118060061700_bib5","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1148\/radiol.2313030521","article-title":"Proteoglycan loss in human knee cartilage: quantitation with sodium MR imaging - 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