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Title: Fibroblast Growth Factor 2 (FGF2) in cartilage injury and repair
Author: Khan, Sumayya Nafisa
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Fibroblast Growth Factors (FGFs) are important pleiotropic growth factors with a proven role in joint development and postnatal homeostasis. Previously our group has shown that FGF2 is released upon cartilage injury and Fgf2 knockout (KO) mice develop accelerated osteoarthritis (OA), suggesting it is chondroprotective in vivo. Work from others has shown that the accelerated OA phenotype in the Fgf2 KOs is phenocopied by deletion of Fgfr3 but not Fgfr1, suggesting that the FGFR may determine FGF2's action in the joint. In the work presented here, I investigate the role of FGF2 in promoting enhanced cartilage regeneration. I first explore the control and function of different FGF receptors (FGFRs) and ligands; then perform an in vivo model of focal cartilage injury in the Fgf2 KO mouse. FGFR3 mRNA expression levels were rapidly down-regulated by injury in an FGF2-dependent manner, but recovered after chondrocytes were isolated and cultured in vitro. I did not observe significant differences in intracellular signalling or expression of a panel of FGF-dependent genes using receptor selective mutant ligands. In vivo, Fgf2 KO mice failed to repair focal cartilage defects compared with wild-type (WT) controls. Mesenchymal stem cells (MSCs) were activated by FGF2; leading to enhanced scratch assay closure and keeping cells in a more motile state but not in promoting cell adhesion to damaged tissue. FGF2 suppressed chondrogenesis of MSCs in vitro. Taken together, I identified a primary role for FGF2 in promoting intrinsic cartilage repair, which may be due to local activation of MSCs. These results provide mechanistic insights into how cartilage repairs and may have important clinical implications.
Supervisor: Vincent, Tonia Sponsor: Kennedy Trust ; Arthritis Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Molecular and Cellular Medicine