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Penrith, Australia

Demontiero O.,University of Sydney | Vidal C.,University of Sydney | Duque G.,Nepean Clinical School
Therapeutic Advances in Musculoskeletal Disease | Year: 2012

It is well known that the underlying mechanisms of osteoporosis in older adults are different than those associated with estrogen deprivation. Age-related bone loss involves a gradual and progressive decline, which is also seen in men. Markedly increased bone resorption leads to the initial fall in bone mineral density. With increasing age, there is also a significant reduction in bone formation. This is mostly due to a shift from osteoblastogenesis to predominant adipogenesis in the bone marrow, which also has a lipotoxic effect that affects matrix formation and mineralization. We review new evidence on the pathophysiology of age-related bone loss with emphasis upon the mechanism of action of current osteoporosis treatments. New potential treatments are also considered, including therapeutic approaches to osteoporosis in the elderly that focus on the pathophysiology and potential reversal of adipogenic shift in bone. © The Author(s), 2011. Source

Gu B.J.,Nepean Clinical School | Saunders B.M.,University of Sydney | Jursik C.,Nepean Clinical School | Wiley J.S.,Nepean Clinical School | Wiley J.S.,University of Melbourne
Blood | Year: 2010

Phagocytosis of nonopsonized bacteria is central to innate immunity, but its regulation is less defined. We show that overexpression of the P2X 7 receptor greatly augments the phagocytosis of nonopsonized beads and heat-killed bacteria by transfected HEK-293 cells, whereas blocking P2X 7 expression by siRNA significantly reduces the phagocytic ability of human monocytic cells. An intact P2X7-nonmuscle myosin complex is required for phagocytosis of nonopsonized beads because activation of P2X 7 receptors by adenosine triphosphate (ATP), which dissociates myosin IIA from the P2X7 complex, inhibits this phagocytic pathway. Fresh human monocytes rapidly phagocytosed live and heat-killed Staphylococcus aureus and Escherichia coli in the absence of serum, but the uptake was reduced by prior incubation with ATP, or P2X7 monoclonal antibody, or recombinant P2X7 extracellular domain. Injection of beads or bacteria into the peritoneal cavity of mice resulted in their brisk phagocytosis by macrophages, but injection of ATP before particles markedly decreased this uptake. These data demonstrate a novel pathway of phagocytosis of nonopsonized particles and bacteria, which operate in vivo and require an intact P2X 7-nonmuscle myosin IIA membrane complex. The inhibitory effect of ATP on particle uptake by the macrophage is regulated by the P2X7 receptor and defines this phagocytic pathway. © 2010 by The American Society of Hematology. Source

Gu B.J.,Nepean Clinical School | Sun C.,Nepean Clinical School | Valova V.A.,Childrens Medical Research Institute | Skarratt K.K.,Nepean Clinical School | Wiley J.S.,Nepean Clinical School
Molecular Biology Reports | Year: 2010

The human P2X4 purinergic receptor is an ATP gated cation-selective channel, which can be upregulated following nerve injury or stimulation by various cytokines. However, the transcriptional control of this regulation is unknown. In this study, the transcription initiation site was estimated to be 72 bp upstream of ATG start codon by using a novel sequencing based primer extension method with 5′-FAM tagged primers. To delineate the promoter region of the P2RX4 gene which encodes the P2X4 receptor, we constructed 8 fragments (size range 100-4500 bp) covering the 4.5 Kb upstream region of the P2RX4 gene. A dual-colour luciferase reporter vector system was used to measure the promoter activities in both transfected HEK-293 cells and COS-7 cells for each fragment extracted from 5 to 7 randomly picked colonies. The 62 bp sequence upstream of the initiation site showed promoter activity. A putative GATA-2 binding site (-29 to -20) within this region was required for high promoter activity and GATA-2 was found to be one of the transcriptional factors binding to P2RX4 promoter by both fluorescent super electrophoresis mobility shift assay and immunoprecipitation using streptavidin coated Dynabeads and biotin-labeled double-strand DNA probes. A single nucleotide polymorphism with minor allele frequency of 0.23 was found within the GATA-2 binding site of P2RX4 promoter region which significantly reduced gene transcription. In conclusion, our data has identified the first transcription factor involved in P2X receptor expression. © 2009 Springer Science+Business Media B.V. Source

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