Publication: Hydroxy group requirement for halofuginone-dependent inhibition of muscle fibrosis and improvement of histopathology in the mdx mouse model for Duchenne muscular dystrophy
Authors
Wellner, Gili ; Mordechay, Sharon ; Evans, Paul ; Genin, Olga ; Pines, Mark ; Halevy, Orna
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Publisher
Universidad de Murcia. Departamento de Biología Celular e Histología
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DOI
DOI: 10.14670/HH-18-083
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info:eu-repo/semantics/article
Description
Abstract
In Duchenne muscular dystrophy (DMD),
the progressive loss of muscle and its ability to function
is associated with significant fibrosis, representing the
major disease complication in patients. Halofuginone, a
halogenated analog of the naturally occurring
febrifugine, has been shown to prevent fibrosis in
various animal models, including those of muscular
dystrophies. Here, two optically active enantiomers of
deoxyhalofuginone—a halofuginone analogue in which
the hydroxy group in position 3 was removed from the
piperidinyl entity—were evaluated with respect to their
effect on muscle histopathology in mdx mice. Male mdx
mice were treated with either deoxyhalofuginone (as
single enantiomers or in racemic form), or halofuginone,
for 10 weeks, starting at the age of 4 weeks.
Halofuginone caused a significant reduction in total
collagen content, degenerative areas, as well as in
utrophin and phosphorylated-Smad3 levels in the mdx
diaphragms. However, neither the deoxyhalofuginone
enantiomers, nor its racemic form had any effect on
these parameters. A positive effect of the
deoxyhalofuginone (+)-enantiomer was observed on
myofiber diameters; however, it was lesser than that of
halofuginone. It is concluded that the hydroxy group
plays a key role in halofuginone’s effects related to
fibrosis in DMD, and points towards the transforming
growth factor β/Smad3 signaling pathway being
involved in this inhibition. Elucidation of the
structure–function relationship of halofuginone, in
relation to inhibiting fibrosis in muscular dystrophies, is
of the utmost importance for creating the next generation
of anti-fibrotic therapies that will be more efficacious
and less toxic, hence improving life quality of patients.
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