AbstractDuchenne muscular dystrophy (DMD) is an inherited, lethal disorder characterised by progressive muscle degeneration and associated bone abnormalities. It has previously demonstrated that P2RX7, a purinergic receptor, contributed to the pathogenesis of DMD, and found that P2RX7 ablation alleviated the severity of the disease. In this work a dystrophic mdx mouse crossed with the global P2RX7 receptor has been used to generate a knockout mouse model (mdx/P2X7-/-), and compared its morphometric, mechanical and tissue properties against those of mdx,a mouse model without the dystrophin protein, as well as a wild type (WT) and aP2RX7 knockout (P2X7-/-). Micro-computed tomography (μCT), three-point bending testing, scanning electron microscopy (SEM) and nanoindentation were utilised in the study. The bones were analysed at approximately 4 weeks of age to examine the impact of P2RX7 ablation on the bone properties during the acute disease phase, before muscle wasting is fully developed.
The results show that P2RX7 purinoceptor ablation has produced improvement or significant improvement in some of the morphological, mechanical and tissue properties of the dystrophic bones examined. Specifically, although the ablation produced smaller bones with significantly lower total cross-section area (Tt.Ar) and Second Moment of Area (SMA), significantly higher cortical bone area (Ct.Ar),cortical bone area ratio (Ct.Ar/Tt.Ar) and trabecular bone volume fraction (BV/TV)are found in the mdx/P2X7-/- mice than in any other types. Further, the mdx/P2X7-/- bones have relatively higher average flexural strength, work-to-fracture and significantly higher strain to failure compared with those of mdx, suggesting greater resistance to fracture. Indentation modulus, elasticity and creep are also significantly improved in the knockout cortical bones over those of mdx. These findings seem to suggest that specific pharmacological blockade of P2RX7 may improve dystrophic bones, with a potential for therapeutic application in the treatment of the disease.
|Date of Award||Nov 2016|
|Supervisor||Jie Tong (Supervisor), Darek Gorecki (Supervisor) & Matt Guille (Supervisor)|