Bioavailability of matrix-bound growth factors in cartilage injury

Thesis

Articular cartilage is a dense extracellular matrix-rich tissue that degrades following chronic mechanical stress, resulting in osteoarthritis. In this work, hepatoma-derived growth factor, previously uncharacterised in cartilage, was discovered to be bound to extracellular matrix heparan sulfate in cartilage. Previously described pericellular matrix growth factors fibroblast growth factor 2 (FGF2) and connective tissue growth factor (CTGF/CCN2), along with hepatoma-derived growth factor (HDGF) were all rapidly released upon injury, independent of cellular viability, and were displaced by exogenous NaCl. I hypothesised that matrix sodium, sequestered within the further removed, aggrecan-rich matrix, was responsible for displacing growth factors upon injury, thereby enhancing their bioavailability. This was confirmed by showing that NaCl was able to release growth factors from cartilage. Furthermore, growth factor release was abrogated by interleukin-1 mediated depletion of matrix aggrecan and sodium, and also in severely damaged human osteoarthritic cartilage with reduced matrix sodium. Finally, a flux in free matrix sodium upon mechanical compression of cartilage was directly visualised by 23Na-MRI imaging. These data corroborate an increase in free matrix sodium upon mechanical injury, able to displace heparan sulfate-bound growth factors in healthy cartilage, which is lost in osteoarthritis. Preliminary data after inducing osteoarthritis in Hdgf -/- mice indicated that HDGF, like FGF2, is chondroprotective in vivo, with putative proliferative effects on mesenchymal stem cells. Together, these results describe a novel intrinsic repair mechanism, mediated by free sodium, in which heparan sulfate-bound growth factors are released from cartilage upon injurious load. They identify aggrecan as a depot for sequestered sodium, and explain why osteoarthritic tissue loses its ability to repair. Treatments that restore matrix sodium to allow appropriate release of growth factors upon load may therefore restore intrinsic cartilage repair in osteoarthritis.

Authors: Keppie, SJ

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: growth factor; cartilage; injury; osteoarthritis; extracellular matrix
• Subjects: Biomedicine; Interdisciplinary Bioscience