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dc.contributor.supervisorHu, Bing
dc.contributor.authorGrayson, Portia
dc.contributor.otherFaculty of Healthen_US

The periodontium is a dynamic tissue that undergoes constant remodeling to maintain its structure and function. There is much evidence in the literature that autophagy can be activated by both mechanical stretching and inflammation, however the mechanisms involved are highly context dependent. Autophagy may also be important for bone remodeling in the oral cavity. Two scenarios where bone remodeling is key to the physiological outcome are orthodontic tooth movement and inflammatory-induced periodontal disease. This thesis aims to investigate the hypothesis that autophagy is involved in bone remodeling during orthodontic tooth movement and periodontal disease. While the stem cells concerned in both osteogenesis and osteoclastogenesis are different, they both originate from the bone marrow, therefore the same primary human bone marrow cells containing the specific stem cell populations required for osteogenesis or osteoclastogenesis were used to establish in vitro models for mechanical strain and chronic inflammation, and the activation and differentiation of these bone marrow derived cells were analysed in response to the conditions created in these model systems. Orthodontic tooth movement invokes constant mechanical force onto the periodontium, with tensile stretching force initiating osteogenesis. Mechanical strain is also linked to an increase in autophagy, a cellular degradation pathway that may be protective or can result in cell death. The hypothesis was that cells exposed to tensile strain undergo an altered state of autophagic flux which contributes to osteogenesis. In vivo and in vitro models of tooth movement were used to analyse osteogenic and autophagy marker expression. Initially tensile strain was found to increase autophagy but decrease expression of osteogenic markers. However, by 24 hours there was a decrease in autophagy and osteogenesis marker expression was increased. Artificially activating autophagy in cells undergoing mechanical stretching resulted in enhanced Runt-related transcription factor 2 (RUNX2) expression, a marker of osteogenic differentiation. Autophagy activation is perhaps a protective mechanism as an initial response to mechanical strain, after which osteogenesis may occur. Patients undergoing orthodontic treatment are at risk of developing periodontitis, a chronic inflammatory disease caused by the presence of Gram-negative bacteria leading to inflammation of the periodontium. It is also clear that disease susceptibility and progression are affected by host factors, however the mechanisms behind this are unknown. Lipopolysaccharide (LPS) tolerance has been demonstrated in many chronic inflammatory diseases and may alleviate or exacerbate disease, but its role in periodontitis is not fully established. The hypothesis was that periodontitis results in LPS tolerance which affects osteoclastogenesis. Hyaluronan (HA) signalling was explored as a potential mechanism, as HA synthesis is upregulated in chronic inflammation. This thesis demonstrates that inflammatory monocytes increase HA synthesis in response to LPS, and that HA enhances differentiation of osteoclast precursors. However, LPS tolerance of inflammatory monocytes resulted in a rapid reduction in HA synthesis, which may be autophagy-dependent. This reduction in HA synthesis resulted in a reduction in osteoclast differentiation, which may explain why periodontal disease associated alveolar bone loss does not always occur to the same severity in different patients. In conclusion, autophagy was found to have roles in the regulation of osteogenesis and osteoclastogenesis under tensile strain and chronic inflammation, respectively, and therefore may be an appropriate future target for pharmaceutical intervention.

dc.publisherUniversity of Plymouth
dc.subjectMechanical Strainen_US
dc.titleThe role of autophagy in protecting periodontium integrity, and lipopolysaccharide-induced osteoclast differentiationen_US
dc.rights.embargoperiod12 monthsen_US

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