Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

Protease-activated receptor-2 exacerbates bone and muscle pathology in a mouse model of Duchenne muscular dystrophy (#62)

Neda Taghavi Esfandouni 1 , Reza Sanaei 1 , Samuel S Chrishan 2 , Charles N Pagel 1 , Eleanor J Mackie 1
  1. Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia
  2. Pharmacology, Monash University, Clayton, Victoria, Australia

Duchenne muscular dystrophy (DMD) is associated with osteoporosis, and dystrophic (dystrophin-deficient) mdx mice show reduced bone mass characterised by decreased mineral apposition and elevated bone resorption. We investigated a potential role of the G-protein-coupled receptor protease-activated receptor-2 (PAR2) in the muscle and bone pathology associated with DMD, using PAR2-null-mdx mice. Limb and diaphragm muscles, tibiae and serum of male PAR2-null-mdx and littermate mdx mice were examined every 4 weeks from just after the onset of muscle pathology (4 weeks) until 20 weeks of age. From 8 weeks, in all muscles examined histologically, the area of active inflammation and number of damaged fibres were lower in PAR2-null-mdx mice compared to mdx mice, although the number of mast cells was higher (e.g. 2.8-fold higher at 8 weeks in diaphragm muscle, P<0.0001). Hydroxyproline content in the diaphragm (indicative of fibrosis) was lower in PAR2-null-mdx than in mdx mice from 12 weeks onwards (27% lower at 20 weeks, P<0.01). PAR2-null-mdx mice showed significantly higher grip strength and lower fatiguability from 8 weeks of age (41% less fatigue, P<0.001, at 20 weeks). Micro-CT evaluation of the tibial metaphysis at 20 weeks of age showed that BV/TV, trabecular number and trabecular thickness were higher (by 80%, 23% and 23%, respectively; all P<0.01) and trabecular separation was lower (14%, P<0.05) in PAR2-null-mdx than in mdx mice. The serum concentrations of IL6 (88%, P<0.01), active TGFβ (19%, P<0.01) and RANKL (37%, P<0.05), and the RANKL/OPG ratio (49%, P<0.01) were lower in PAR2-null-mdx mice compared to mdx mice at 20 weeks. These results indicate that PAR2 activation contributes to muscle inflammation in dystrophin-deficient mice and suggest that the associated bone pathology is caused at least in part by muscle inflammation. PAR2 antagonists may help ameliorate the effects of dystrophin deficiency without the detrimental effects on bone of glucocorticoids.