Inflammasome Increases Muscle Damage in Muscular Dystrophy
Dr. Kanneboyina Nagaraju and colleagues at the Children's National Medical Center, Washington, DC demonstrate that affected muscle may directly contribute to inflammation in muscular dystrophy. Their report can be found in the June 2010 issue of The American Journal of Pathology.
Muscular dystrophy is a group of genetic diseases that result in progressive weakening of the human body, leading to muscle wasting and even the inability to walk. Many patients with muscular dystrophy shown signs of inflammation; however, the mechanisms governing this inflammation in disease pathogenesis remain unexplored.
To investigate the role of the inflammasome, which is responsible for activation of inflammatory processes, in muscular dystrophy, Rawat et al examined the inflammasome platform in mouse and human tissues that develop limb girdle muscular dystrophy type 2B (LGMD2B). They found that components of the inflammasome pathway were upregulated and activated in diseased muscle as compared with control muscle and that primary skeletal muscle cells can secrete inflammatory mediators, directly participating in inflammasome formation. Moreover, diseased muscle cells expressed innate immune molecules, suggesting that affected muscle may directly contribute to inflammation in muscular dystrophy and providing a new therapeutic target for LGMD2B.
Dr. Nagarju's group concludes that "it is likely that age-related physiological changes in the skeletal muscle, together with environmental insults, can initiate the disease process in LGMD2B. - [They] propose that the increase in vesicular trafficking and plasma membrane repair defects associated with LGMD2B results in the release of ATP and other endogenous danger/alarm signals (e.g, HMGB1, S100 proteins). These molecules, in turn, bind to their cellular receptors (toll-like receptors, P2X7 receptors) and activate the inflammasome pathway. - Downstream processes [may then] activate not only inflammation and fibrosis but also lead to significant muscle fiber damage and dysfunction."
Rawat R, Cohen TV, Ampong B, Francia D, Pons A, Hoffman EP, Nagaraju K: Inflammasome up-regulation and activation in dysferlin-deficient skeletal muscle. Am J Pathol 2010, 176: 2891-2900
New Model for Chronic Wasting Disease
A group led by Dr. Edward Hoover at Colorado State University, Fort Collins, CO have generated a mouse model of cervid chronic wasting disease. They present these findings in the June 2010 issue of The American Journal of Pathology.
Chronic wasting disease is a fatal prion-induced disease, similar to mad cow disease, that affects cervids such as deer, elk, and moose. It is a neurodegenerative disease typified by chronic weight-loss leading to death. Prions are infectious agents composed primarily of proteins that are thought to be propagated by transmitting a mis-folded protein state. Due to the lack of an appropriate small animal model, little is known about cervid chronic wasting disease.
Using a mouse model of chronic wasting disease that expresses cervid prion protein (PrP), Seelig et al examined the susceptibility, pathogenesis, and transmission of cervid chronic wasting disease. They found that cervid PrPC (protease-sensitive PrP) was expressed in a number of different tissues, including lymphoid, nervous, hematopoietic, endocrine, and certain epithelial tissues, in this model. Additionally, disease could be transferred by various infectious methods, including injection into the brain, blood stream, and gut. It could also be transmitted orally, although the oral route required a larger infecting dose. Furthermore, this disease could be transferred between animals without experimental intervention to uninfected mice, highlighting the suitability of this system in studying cervid transmissible spongiform encephalopathy.
Dr. Hoover's group suggests that "cervidized transgenic mice substantially recapitulate the clinical, neuropathologic, and PrPRES tropism and transmission patterns reported in the native cervid species and [that] studies in Tg[CerPrP] mice can provide additional insights into the trafficking, shedding, and lateral transmission of [chronic wasting disease] prions."
Seelig DM, Mason GL, Telling GC, Hoover EA: Pathogenesis of Chronic Wasting Disease in Cervidized Transgenic Mice. Am J Pathol 2010 176: 1785-2797
New Target May Inhibit Metastatic Breast Cancer
Researchers led by Dr. Yves St-Pierre at INRS-Institut Armand-Frappier, Qu-bec, Canada implicate galectin-7 as a breast cancer differentiation marker. They report their data in the May 2010 issue of The American Journal of Pathology.
Breast cancer is the second-most common type of non-skin cancer and the fifth-most common cause of cancer death world-wide. Breast cancer is 100-times more common in women than in men.