Parkar, Mohammed H; (2000) Cellular and molecular processes in periodontal growth and renewal. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Chronic inflammatory periodontal diseases (CIPDs) are considered to be mediated by cytokines in response to dental plaque, involve destruction of connective tissue, bone breakdown and ultimately tooth loss. In contrast, the repair and regeneration of periodontal tissues are wound healing processes characterised by active cell growth and the production of new extracellular matrix (ECM). In addition, in gingival hyperplasia (GH), a pathological condition resulting from the administration of certain immunosuppresants, anti-epileptic drugs and calcium channel-blocking agents, there is enlargement of the gingival connective tissue and excessive accumulation of ECM. As in other hyperplastic lesions, GH has been associated with growth factors and anabolic steroid hormones, which are known to regulate cell proliferation, differentiation and the synthesis of ECM components. The actions of these factors are mediated through specific cell surface and intracellular receptors, although their role in periodontal tissues has not been well defined. This study has examined the expression of androgen and growth factor receptors in gingival fibroblasts (GF) and in periodontal ligament (PDL) cells Analysis using the reverse-transcribed polymerase chain reaction (RT-PCR) established that the androgen receptor (AR) is expressed by both types cell. However, the levels of AR were found to be similar in both normal and GH tissues, while AR levels in normal GF in vitro were unaffected by the drugs which cause GH in vivo. In contrast, the activity of the AR may be important in GH, since androgens were found to down-regulate the interleukin-6 (IL-6), a cytokine involved in connective tissue turnover. Growth factor receptor expression was analysed by flow cytometry (FCM) and the results showed that although the ?-receptor for platelet-derived growth factor (PDGF) was expressed by all the cells, receptors for transforming growth factor (TGF-?) type I and II, fibroblast growth factor (FGF) and insulinlike growth factor (IGF) were differentially expressed by GF and PDL cells. In contrast, neither the GF nor PDL cells expressed either the PDGF receptor ? or the epidermal growth factor (EGF) receptor. The cellular and molecular events associated with periodontal wound healing may be similar to those occurring during embryonic development, in which the ECM protein fibronectin (FN) plays an important role. This aspect of the study investigated the expression of FN molecular isoforms in periodontal tissues. All embryonic isoforms were found to be expressed in healthy gingiva, periodontal ligament and GH tissues whereas CIPD tissues generated only the low molecular weight adult isoforms. Furthermore, certain growth factors elicited pronounced up-regulation of the embryonic FN isoforms in PDL cells, which may be of particular relevance to periodontal regeneration. In order to develop in vitro models for the investigation of periodontal disease and regeneration, long-term cell lines of GF and PDL cells were obtained by retroviral transduction of primary cells with a temperature-sensitive oncogene, the SV40 large T antigen. This was carried out in order to provide a continuous source of cells for the investigation of certain key proteins which have a fundamental role in periodontal wound healing. The results of this study have demonstrated that the activity of the AR may have an important role in periodontal growth. Furthermore, the periodontal cells differentially express key growth factor receptors and the PDL cells produce embryonic FN isoforms in response to certain growth factors which are likely to be involved in periodontal growth and renewal.

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