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Title: Hypoxia related function in human osteoarthritic cartilage
Author: Hipkiss, Leo William Edward
ISNI:       0000 0004 8502 8968
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Articular cartilage is an avascular tissue, and therefore, at least in large animals, functions in a hypoxic environment. In healthy human cartilage, chondrocytes exhibit a well-adapted hypoxic response. Previous work in our laboratory has shown that hypoxia in healthy human articular chondrocytes (HACs) increases anabolic function (SOX9, COL2A1, ACAN) via HIF-2α and decreases catabolism (reducing MMP13 and ADAMTS5) predominantly via HIF-1α. Inhibition of HIF-targeting hydroxylase PHD2 was also identified as a potential means to induce cartilage repair by enhancing HIF-2α levels subsequently increasing anabolism via SOX9. In contrast, evidence from murine studies has suggested HIF-2α as a catabolic regulator in the progression of OA, targeting key catabolic enzymes MMP13 and ADAMTS5, thus indicating HIF-2α as a potentially relevant therapeutic target in OA. The role of hypoxia and HIF activity in human OA cartilage and chondrocytes is less clearly understood, and hence was the focus of the current study. In this study the general response of key cartilage genes, in primary OA HACs, to hypoxia are shown to be beneficial to the chondrocyte phenotype (as it is in healthy HACs). Hypoxia in OA HACs increases levels of SOX9 by 125% and subsequently increases the downstream cartilage matrix gene COL2A1 by 215% compared to levels observed in normoxia. Additionally, it is reported that the hypoxia-mediated downregulation of MMP13 and ADAMTS5 by 32% and 45% respectively. However, it is noted that TIMP3 is not induced by hypoxia in OA HACs indicating a potentially reduced protective capacity compared to healthy cartilage. Interestingly, it is observed that HIF-1α is the predominant isoform responsible for the induction of SOX9 in OA HACs (as opposed to HIF-2α in healthy HACs) noting the depletion of HIF-1α reduces SOX9 by 54% and 61% in normoxia and hypoxia respectively. Importantly, results represent no evidence of a HIF-2α dependent induction of catabolic factors in OA HACs, but rather a potentially anti-catabolic role reducing ADAMTS5 and MMP13 levels by 111% and 78% respectively in hypoxia. Furthermore, the results shows that, whilst PHD2 depletion on its own is insufficient, combined HIF-targeting hydroxylase inhibition (via DMOG) can enhance the beneficial effects of hypoxia observed in OA HACs (increasing SOX9 levels 2.36 fold above typically observed by hypoxia alone). Therefore, a combined inhibition of the PHDs represents a potential means of increasing cartilage matrix production in an OA setting.
Supervisor: Murphy, Chris Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available