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- W2891076199 abstract "Clinical studies have shown that osteoporosis and muscle degeneration can occur in tandem following neuromuscular diseases. The receptor-activator of nuclear factor κB (RANK), the receptor-activator of nuclear factor κB ligand (RANKL), and osteoprotegerin (OPG) triad, a key pathway for bone regulation, is involved in Duchenne muscular dystrophy physiopathology. OPG, a decoy receptor for RANKL, the truncated (TR-OPG-Fc) or full-length OPG (FL-OPG-Fc) fused with an Fc fragment of IgG1 can inhibit RANKL/RANK interactions in vivo or in vitro. TR-OPG-Fc contains only 4 cysteine-rich RANKL domains while FL-OPG-Fc contains 4 cysteine-rich RANKL domains, 2 TRAIL death domains and 1 heparin-binding domain. We have shown that a 10 day treatment with FL-OPG-Fc during the first acute phase of degeneration in dystrophin-deficient mdx mice completely restored force and resistance to eccentric contractions of fast-twitch muscle. Because FL-OPG-Fc was superior to muscle specific deletion of RANK or anti-RANKL, anti-TRAIL, TR-OPG-Fc treatments, we hypothesized that the heparin-binding domain found in FL-OPG-Fc interacts directly with muscle. WB and confocal microscopy demonstrated that FL-OPG-Fc, but not TR-OPG-Fc, binds to C2C12 myotube. We next showed that heparinase III, which cleaves heparan sulfate chains, reduces FL-OPG-Fc binding by 50%. To further support the importance of the heparin domain, FL-OPG-Fc was co-incubated with equal concentration of heparin, which abrogated by 85% its binding ability. Next, using ex vivo contractile properties of isolated fast-twitch EDL, we showed that a 24h FL-OPG-Fc treatment increased significantly the absolute and specific forces of dystrophic EDL. In conclusion, FL-OPG-Fc, through its heparin-binding domain, binds directly muscle cells and can rapidly increase absolute and specific maximal tetanic forces. Current investigations are directed towards a better understanding of the mechanisms by which FL-OPG-Fc improves dystrophic muscles." @default.
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- W2891076199 date "2018-10-01" @default.
- W2891076199 modified "2023-10-14" @default.
- W2891076199 title "DMD TREATMENT: ANIMAL MODELS" @default.
- W2891076199 doi "https://doi.org/10.1016/j.nmd.2018.06.255" @default.
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