A group led by Dr. Dieter Brömme at the University of British Columbia has demonstrated that glycosaminoglycans (GAGs) contribute to skeletal abnormalities in patients with lysosomal storage diseases. Their report can be found in the November 2009 issue of The American Journal of Pathology.
Mucopolysaccharidoses (MPS) are a group of diseases in which the dysfunction of a lysosomal enzyme results in decreased breakdown of GAGs, a type of carbohydrate, in various tissues. These GAGs then collect in cells, causing severe cellular damage that affects bone, skeletal structure, connective tissue, and organs.
In cells that break down bone, GAGs have been shown to inhibit the function of cathepsin K, an enzyme that breaks down collagen, which leads to insufficient space for new bone formation. As MPS patients have severe deficiencies in bone growth and development, Wilson et al hypothesized that cathepsin K inhibition may contribute to bone pathology in MPS patients. They found that both GAGs and cathepsin K were expressed in bone growth regions of a mouse model of MPS type I and that higher levels of cartilage accumulated in bone growth regions of MPS I mice than in their wild-type counterparts. In addition, cathepsin K-mediated collagen degradation was significantly reduced in bone-resorbing cells from MPS I mice.
Taken together, the data by Dr. Brömme and colleagues suggest that "the decrease in the collagenolytic activity of cathepsin K due to the expression of GAGs will greatly reduce osteoclast function and will thus likely contribute to the skeletal abnormalities observed in MPS I bone."
Wilson S, Hashamiyan S, Clarke L, Saftig P, Mort J, Dejica VM, Brömme D: Glycosaminoglycan-mediated loss of cathepsin K collagenolytic activity in MPS I contributes to osteoclast and growth plate abnormalities. Am J Pathol 2009, 175: 2047-2056
Treating Ovarian Cancer
Dr. Ernst Lengyel and colleagues at The University of Chicago have discovered that vitronectin receptor (αvβ3-integrin) expression significantly improved ovarian cancer patient prognosis. They present these findings in the November 2009 issue of The American Journal of Pathology.
Ovarian cancer affects 1 out of 40-60 women. Because early stages of ovarian cancer are often asymptomatic, it is frequently discovered after metastasis to other tissues. The five-year survival rate for all stages of ovarian cancer is 45.5%.
Vitronectin receptor expression plays a key role in tumor progression in breast cancer and melanoma as well as in tumor angiogenesis in endothelial cells. Kaur et al therefore examined the function of this molecule in ovarian cancer. In contrast to other tumor models, ovarian cancer cells that expressed high levels of αvβ3-integrin showed impaired signs of metastasis and proliferated at a slower rate. Conversely, inhibiting α3-integrin increased ovarian cancer cell invasion and proliferation. In addition, high α3-integrin expression significantly improved ovarian cancer patient prognosis.
Kaur et al suggest that "when expressed on tumor cells, αvβ3-integrin can be a marker for a less aggressive cancer cell population and therefore, might not be an appropriate target for inhibition."
Kaur S, Kenny HA, Jagadeeswaran S, Zillhardt MR, Montag AG, Kistner E, Yamada SD, Mitra AK, Lengyel E: α3-integrin expression on tumor cells inhibits tumor progression, reduces metastasis, and is associated with a favorable prognosis in patients with ovarian cancer. Am J Pathol 2009, 175: 2178-2190
CpG DNA Therapy for Alzheimer Disease
Dr. Yukiko Doi and colleagues at Nagoya University have found that CpG DNA may be a therapeutic candidate for treatment of Alzheimer disease. They report their data in the November 2009 issue of The American Journal of Pathology.
Alzheimer disease is the most common form of dementia, affecting approximately 1.6% of the population in the United States (nearly 19% in the 75-84 age group). It is an incurable, degenerate, and terminal disease thought to be caused by accumulation of oligomeric amyloid β (oAβ).
Microglia are the resident immune cells in the central nervous system; they remove damaged neurons, plaques, and infectious agents from the brain and spinal cord. Microglia cluster around senile Aβplaques in Alzheimer disease patients; however, the role of microglia in oAβtoxicity remains unclear. Doi et al discovered that microglial activation with unmethylated CpG DNA, which binds to an immune receptor on microglia, prevented oAβtoxicity and enhanced oAβ peptide clearance in culture. Furthermore, injection of CpG DNA directly into the brain mitigated both cognitive impairment and learning defects in a mouse model of Alzheimer disease. CpG DNA may therefore be a therapeutic candidate for treatment of Alzheimer disease.
Dr. Doi and colleagues conclude that "CpG, especially class B and C, may also be effective therapeutic agents against oAβ1-42 neurotoxicity in [Alzheimer disease]."
Doi Y, Mizuno T, Maki Y, Jin S, Mizoguchi H, Ikeyama M, Doi M, Michikawa M, Takeuchi H, Suzumura A: Microglia activated with the toll-like receptor 9 ligand CpG attenuate oligomeric amyloid β neurotoxicity in in vitro and in vivo models of Alzheimer's disease. Am J Pathol 2009, 175: 2115-2126
Eosinophils in Allergy and Asthma
Researchers led by Dr. Redwan Moqbel at the University of Alberta, University of Western Australian, and Princess Margaret Hospital in Perth, Australia have discovered that eosinophils may play a pivotal role in immune development. These results are presented in the November 2009 issue of The American Journal of Pathology.
Asthma and allergic disease occur when the immune system improperly responds to harmless environmental substances such as pollen or mold. Common allergic reactions include eczema, hives, hay fever, asthma, food allergies, and reactions to the venom of stinging insects such as wasps and bees.
Immune responses can be classified as Th1 or Th2 based on the type of inflammation and molecules secreted after stimulation. Th1 immune responses traditionally fight intracellular infections such as bacterial and viral infections, whereas Th2 responses are specialized for large parasites such as worms. Asthma and allergic disease result from an improper Th2 immune response.
Although eosinophils, a type of immune cell, have long been considered to mediate allergic and asthmatic Th2 immune responses, they may also play a role in determining the switch between Th1 and Th2 immune responses. Tulic et al therefore examined the development of eosinophils in human children. They observed an age-dependent decrease in the number of eosinophils in the thymus, an organ where early Th1/Th2 differentiation may occur, suggesting an early role of eosinophils in Th2 bias.
Dr. Moqbel's group suggests that "functional thymic IDO+ eosinophils during human infant life may have an immunomodulatory role in Th2 immune responses."
Tulic MK, Sly PD, Andrews D, Crook M, Davoine F, Odemuyiwa SO, Charles A, Hodder ML, Prescott SL, Holt PG, Moqbel R: Thymic indoleamine 2,3-dioxygenase-positive eosinophils in young children: potential role in maturation of the naïve immune system. Am J Pathol 2009, 175: 2037-2046
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