Impact of P2RX7 ablation on the morphological, mechanical and tissue properties of bones in a murine model of duchenne muscular dystrophy

Mohamad, N. S.; Sinadinos, A.; Górecki, D. C.; Zioupos, P.; Tong, J.

Abstract

Duchenne muscular dystrophy (DMD) is an inherited, lethal disorder characterised by progressive muscle degeneration and associated bone abnormalities. We have previously demonstrated that P2RX7 purinergic receptors contribute to the pathogenesis of DMD, and found that P2RX7 ablation alleviated the severity of the disease. In this work we have used a dystrophic mdx mouse crossed with the global P2RX7 receptor to generate a knockout mouse (mdx/P2X7−/−), and compared its morphometric, mechanical and tissue properties against those of mdx, as well as the wild type (WT) and the P2RX7 knockout (P2X7−/-). Micro-computed tomography (µCT), three-point bending testing, scanning electron microscopy (SEM) and nano-indentation 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, the mechanical and the 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 area fraction (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.

Citation

Mohamad, N. S., Sinadinos, A., Górecki, D. C., Zioupos, P., & Tong, J. (2016). Impact of P2RX7 ablation on the morphological, mechanical and tissue properties of bones in a murine model of duchenne muscular dystrophy. Journal of biomechanics, 49(14), 3444-3451. https://doi.org/10.1016/j.jbiomech.2016.09.016

• Journal Article Type: Article
• Acceptance Date: Sep 12, 2016
• Online Publication Date: Sep 15, 2016
• Publication Date: Oct 3, 2016
• Deposit Date: Oct 24, 2023
• Journal: Journal of Biomechanics
• Print ISSN: 0021-9290
• Electronic ISSN: 1873-2380
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 49
• Issue: 14
• Pages: 3444-3451
• DOI: https://doi.org/10.1016/j.jbiomech.2016.09.016
• Public URL: https://hull-repository.worktribe.com/output/4424624