uPA deficiency exacerbates muscular dystrophy in MDX mice.
Duchenne muscular dystrophy (DMD) is a fatal and incurable muscle degenerative disorder. We identify a function of the protease urokinase plasminogen activator (uPA) in mdx mice, a mouse model of DMD. The expression of uPA is induced in mdx dystrophic muscle, and the genetic loss of uPA in mdx mice exacerbated muscle dystrophy and reduced muscular function. Bone marrow (BM) transplantation experiments revealed a critical function for BM-derived uPA in mdx muscle repair via three mechanisms: (1) by promoting the infiltration of BM-derived inflammatory cells; (2) by preventing the excessive deposition of fibrin; and (3) by promoting myoblast migration. Interestingly, genetic loss of the uPA receptor in mdx mice did not exacerbate muscular dystrophy in mdx mice, suggesting that uPA exerts its effects independently of its receptor. These findings underscore the importance of uPA in muscular dystrophy.
Suelves
Mònica
M
Program on Differentiation and Cancer, Center for Genomic Regulation, E-08003, Barcelona, Spain.
Vidal
Berta
B
Serrano
Antonio L
AL
Tjwa
Marc
M
Roma
Josep
J
López-Alemany
Roser
R
Luttun
Aernout
A
de Lagrán
María Martínez
MM
Díaz-Ramos
Angels
A
Díaz
Maria Angels
MA
Jardí
Mercè
M
Roig
Manuel
M
Dierssen
Mara
M
Dewerchin
Mieke
M
Carmeliet
Peter
P
Muñoz-Cánoves
Pura
P
D000818:Animals; D016026:Bone Marrow Transplantation; D002465:Cell Movement; D002478:Cells, Cultured; D005337:Fibrin / Q000378:metabolism; D008264:Macrophages / Q000502:physiology; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D032446:Myoblasts / Q000378:metabolism* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency*