January 2, 2012
A Firmer Understanding Of Muscle Fibrosis
Researchers describe how increased production of a microRNA promotes progressive muscle deterioration in a mouse model of Duchenne muscular dystrophy (DMD), according to a study published online on January 2 in the Journal of Cell Biology (www.jcb.org).
As DMD patients age, their damaged muscle cells are gradually replaced by collagen-rich, fibrous tissue. This muscle fibrosis is partly induced by the growth factor TGF-beta, which is highly activated in DMD patients, though exactly how this cytokine promotes fibrogenesis is unclear. Pura MuÃ±oz-CÃ¡noves and colleagues examined the role of miR-21, a microRNA whose production is stimulated by TGF-beta signaling.
The researchers also discovered that TGF-beta activity and miR-21 production were regulated by the balance of two extracellular factors: uPA–a protease that activates TGF-beta–and its inhibitor PAI-1. mdx mice developed fibrotic muscles more quickly in the absence of PAI-1, but these symptoms could be reversed by inhibiting uPA with a drug or a specific siRNA. In addition to producing more collagen, PAI-1—null fibroblasts also proliferated rapidly because the extra miR-21 induced by active TGF-beta inhibited the tumor-suppressive phosphatase PTEN.
TGF-beta inhibitors prevent muscle fibrosis but have damaging side effects; this study suggests that uPA or miR-21 may make attractive alternative drug targets. MuÃ±oz-CÃ¡noves now wants to investigate the function of miR-21 in other cell types that influence muscle homeostasis, such as the macrophages involved in tissue repair.
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