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Alqallaf, Sayed Mahmood
Languages: English
Types: Doctoral thesis
Subjects: RM
Purinergic P2X7 receptors are ligand-gated ion channels characterized by the formation of a membrane pore upon continuous activation. This receptor has been shown to be expressed and functional in osteoclasts. P2X7 receptor knockout mice studies suggested that this receptor has a role in bone formation. The aim of this project was to characterise the expression and function of P2X7 receptors in human osteoblasts and to investigate the modulation of P2X7 receptor expression and function by oestrogen and glucocorticoids. Reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting were used to study P2X7 receptor expression at the mRNA and protein levels, respectively. P2X7 receptor pharmacology was studied using pore formation and YO-PRO 1 influx in the presence of different agonists and antagonists. The effects of P2X7 receptor activation on physiological aspects of osteoblast function, namely alkaline phosphatase (ALP) production, interleukin-6 (IL-6) and IL-lp release and mineralisation, were also studied. The general findings are: Human osteoblasts (cell lines and primary cells) express functional P2X7 receptors with higher expression seen in primary cells. P2X7 receptor protein is expressed in all the osteoblast-like cell line samples used (lysate, nuclei, and membranes). The functional form of the P2X7 receptor protein appears to correspond to the 67 kDa band and not the 85 kDa band as suggested by the Western blotting results. The pharmacology of P2X7 receptors in human osteoblasts is atypical as evinced by the low affinity of the agonist, benzoyl- benzoyl-adenosine triphosphate (DBzATP) and the weak action of the antagonists, KN62 and brilliant blue-G (BBG). 17p-oestradiol and dexamethasone modulate P2X7 receptor function probably by a non-classical, non-genomic mechanism. ALP production and IL-6 release are increased by P2X7 receptor activation. P2X7 receptor activation appears to decrease mineralisation in primary human osteoblasts. In addition to P2X7 receptors, human osteoblasts express P2X4 and P2X5 receptors. These findings suggest that P2X7 receptors play an important role in osteoblast bone formation and in osteoblast-osteoclast signalling. Targeting P2X7 receptors is a novel approach for the treatment of conditions such as osteoporosis and rheumatoid arthritis. However, further research is needed to develop selective agonists and antagonists.
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