Journal
FUNCTION
Volume 2, Issue 5, Pages -Publisher
OXFORD UNIV PRESS
DOI: 10.1093/function/zqab037
Keywords
Growth Factor; Osteoarthritis; Injury; Repair; Cartilage; Extracellular Matrix; Sodium
Categories
Funding
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/M011224/1]
- Centre for Osteoarthritis Pathogenesis Versus Arthritis [20205, 21621]
- National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC)
- Medical Research Council [G1001398, MC PC 15074]
- Arthritis Research UK [20714]
- Leverhulme Trust Visiting Professorship [VP2-2015-025]
- MRC [G1001398, MC_PC_15074] Funding Source: UKRI
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This study identifies three pro-regenerative factors released from articular cartilage upon mechanical injury, with sodium playing a crucial role in this process. The release of growth factors is influenced by the migration of sodium, controlled by matrix stiffness. Aggrecan serves as a depot for sequestered sodium, impacting the ability of cartilage to repair itself.
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-TGF beta), 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 Na-23 -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. 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. [GRAPHICS]
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