A protein called osteopontin has been implicated as a cause of some of the detrimental inflammation and scarring ("fibrosis") of muscle tissue that takes place in Duchenne muscular dystrophy (DMD). Eliminating osteopontin was beneficial to mice with a DMD-like disease, and the researchers concluded that reducing osteopontin should be investigated as a possible therapy for DMD.
Sylvia Vetrone at the University of California-Los Angeles (UCLA) and colleagues published their findings online May 18, 2009, in the Journal of Clinical Investigation.
The eight-person study team was coordinated by Melissa Spencer at UCLA and included Carrie Miceli, a UCLA immunologist whose contribution Spencer called "hugely significant." Also on the team was Eric Hoffman, who has MDA support for closely related work at Children's National Medical Center in Washington.
Osteopontin plays a role in promoting tissue damage in autoimmune diseases, disorders in which the immune system mistakenly attacks the body's own tissues, the investigators note.
Although DMD is a genetic disease whose underlying cause is the loss of the muscle protein dystrophin, it shares some features with autoimmune disorders, such as inflammatory tissue changes. The inflammatory changes are believed to be secondary to the loss of dystrophin.
The investigators in this study found elevated osteopontin levels in muscle biopsy samples from people with DMD and in the blood and muscles of dystrophin-deficient mice with a disease resembling human DMD. Elevation of osteopontin correlated with progression of the disease process in the mice.
To see the effects of eliminating osteopontin, the researchers bred mice lacking both osteopontin and dystrophin. In these dystrophin-deficient, osteopontin-deficient mice, they saw fewer immune-system cells and more regulatory cells known to dampen the immune response than they saw in the dystrophin-deficient mice. They also saw lower levels of a protein known to cause fibrosis in the mice missing both dystrophin and osteopontin than in the mice missing only dystrophin.
Dystrophin-deficient, osteopontin-deficient mice were stronger than dystrophin-deficient mice when they were tested at 4 and 8 weeks of age.
Although they didn't maintain this strength advantage at 6 months, their diaphragm and heart muscles did show less scarring than those of the dystrophin-deficient mice at the age of 6 months. (Spencer said studies are under way to test diaphragm and heart function in these mice.)
The researchers interpreted these early findings to mean that osteopontin promotes inflammation and contributes to the deposition of scar tissue in dystrophic muscles.
They say their studies suggest that blocking osteopontin "may be a promising therapeutic target for reducing inflammation and fibrosis in individuals with DMD." They note that further studies should be designed to find ways of reducing osteopontin in muscle tissue and to better understand the relationship between osteopontin, regulatory cells and the dystrophic process.