Fibrosis inhibition and muscle histopathology improvement in laminin-alpha2-deficient mice.
In muscular dystrophies (MD) the loss of muscle and its ability to function are associated with fibrosis. We evaluated the efficacy of halofuginone in reducing fibrosis in the dy(2J)/dy(2J) mouse model of congenital MD. Mice were injected intraperitoneally with 5 microg of halofuginone 3 times a week for 5 or 15 weeks, starting at the age of 3 weeks. Halofuginone caused a reduction in collagen synthesis in hindlimb muscles. This was associated with reductions in the degenerated area, in cell proliferation, in the number of myofibers with central nuclei, with increased myofiber diameter, and with enhanced motor coordination and balance. Halofuginone caused a reduction in infiltrating fibroblasts that were located close to centrally nucleated myofibers. Our results suggest that halofuginone reduced the deleterious effects of fibrosis, thus improving muscle integrity. Halofuginone meets the criteria for a novel antifibrotic therapy for MD patients.
Nevo
Yoram
Y
Neuropediatric Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Halevy
Orna
O
Genin
Olga
O
Moshe
Itai
I
Turgeman
Tidhar
T
Harel
Michal
M
Biton
Edva
E
Reif
Shimon
S
Pines
Mark
M
D000818:Animals; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000096:biosynthesis; D005355:Fibrosis / Q000188:drug therapy / Q000473:pathology; D007797:Laminin / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology*; D009137:Muscular Dystrophy, Animal / Q000473:pathology* / Q000628:therapy; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D052999:Quinazolinones / Q000494:pharmacology* / Q000627:therapeutic use; D045442:Rotarod Performance Test
D007797:Laminin; D010880:Piperidines; D052999:Quinazolinones; C102645:laminin alpha 2; D003094:Collagen; C010176:halofuginone