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

Keppie, Stuart J.; Mansfield, Jessica C.; Tang, Xiaodi; Philp, Christopher J.; Graham, Helen K.; Önnerfjord, Patrik; Wall, Alanna; McLean, Celia; Winlove, C. Peter; Sherratt, Michael J.; Pavlovskaya, Galina E.; Vincent, Tonia L.

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 -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.

• Journal Article Type: Article
• Acceptance Date: Jul 30, 2021
• Online Publication Date: Aug 2, 2021
• Publication Date: 2021
• Deposit Date: Sep 9, 2021
• Publicly Available Date: Sep 10, 2021
• Journal: Function
• Electronic ISSN: 2633-8823
• Publisher: Oxford University Press (OUP)
• Peer Reviewed: Peer Reviewed
• Volume: 2
• Issue: 5
• Article Number: zqab037
• DOI: https://doi.org/10.1093/function/zqab037
• Public URL: https://nottingham-repository.worktribe.com/output/6189898
• Publisher URL: https://academic.oup.com/function/article/2/5/zqab037/6335483