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Port Adelaide, Australia

Yang B.,University of Iowa | Kumar S.,SA Pathology and Hanson Institute
Cell Death and Differentiation | Year: 2010

The Nedd4 (neural precursor cell-expressed developmentally downregulated gene 4) family of ubiquitin ligases (E3s) is characterized by a distinct modular domain architecture, with each member consisting of a C2 domain, 2-4 WW domains, and a HECT-type ligase domain. Of the nine mammalian members of this family, Nedd4 and its close relative, Nedd4-2, represent the ancestral ligases with strong similarity to the yeast, Rsp5. In Saccharomyces cerevisiae Rsp5 has a key role in regulating the trafficking, sorting, and degradation of a large number of proteins in multiple cellular compartments. However, in mammals the Nedd4 family members, including Nedd4 and Nedd4-2, appear to have distinct functions, thereby suggesting that these E3s target specific proteins for ubiquitylation. In this article we focus on the biology and emerging functions of Nedd4 and Nedd4-2, and review recent in vivo studies on these E3s. © 2010 Macmillan Publishers Limited All rights reserved. Source

Perilli E.,Flinders University | Parkinson I.H.,SA Pathology and Hanson Institute | Reynolds K.J.,Flinders University
Annali dell'Istituto Superiore di Sanita | Year: 2012

Micro-CT systems are available that facilitate ex vivo examinations of human specimens as big as entire vertebrae, with spatial resolutions in the 10-micrometer range. This opens a new way for looking at entire bones in 3D. Accurate description of the internal microarchitecture of the entire organ can be obtained, at spatial resolutions previously achievable only on excised biopsies. These high resolution scans produce large datasets and come with costs and benefits, which have to be considered in the successful planning of an experiment. The aim of this paper is to present examples of human vertebrae scanned at high resolution (17 μm/pixel), allowing the visualization and quantification of the microarchitecture, and to discuss some aspects of using high resolution scans of such large specimens. The datasets were down-sampled to 34 μm and 68 μm pixel size, and their morphometric parameters compared to those obtained at 17 μm pixel size, in relation to data size and calculation time. Source

Fazzalari N.L.,SA Pathology and Hanson Institute | Fazzalari N.L.,University of Adelaide
Osteoporosis International | Year: 2011

Fracture healing is a multistage repair process that involves complex, well-orchestrated steps initiated in response to tissue injury. The early upregulation of IL-6, osteoprotegerin (OPG), VEGF, and BMPs indicates a central role for these factors in the initiation of cartilage and periosteal woven bone formation. In both callus fracture repair and stress fracture repair, the RANKL/OPG ratio is initially reduced, but peaks earlier in stress fracture healing than callus fracture healing. Though the understanding of the biological processes and molecular signals that coordinate fracture repair has advanced, the cause of variability observed in fracture repair is poorly understood. © International Osteoporosis Foundation and National Osteoporosis Foundation 2011. Source

Fletcher L.,University of Adelaide | Codrington J.,University of Adelaide | Codrington J.,SA Pathology and Hanson Institute | Parkinson I.,SA Pathology and Hanson Institute | Parkinson I.,University of Adelaide
Journal of Materials Science: Materials in Medicine | Year: 2014

As a composite material, cortical bone accumulates fatigue microdamage through the repetitive loading of everyday activity (e.g. walking). The accumulation of fatigue microdamage is thought to contribute to the occurrence of fragility fractures in older people. Therefore it is beneficial to understand the relationship between microcrack accumulation and the fracture resistance of cortical bone. Twenty longitudinally orientated compact tension fracture specimens were machined from a single bovine femur, ten specimens were assigned to both the control and fatigue damaged groups. The damaged group underwent a fatigue loading protocol to induce microdamage which was assessed via fluorescent microscopy. Following fatigue loading, non-linear fracture resistance tests were undertaken on both the control and damaged groups using the J-integral method. The interaction of the crack path with the fatigue induced damage and inherent toughening mechanisms were then observed using fluorescent microscopy. The results of this study show that fatigue induced damage reduces the initiation toughness of cortical bone and the growth toughness within the damage zone by three distinct mechanisms of fatigue-fracture interaction. Further analysis of the J-integral fracture resistance showed both the elastic and plastic component were reduced in the damaged group. For the elastic component this was attributed to a decreased number of ligament bridges in the crack wake while for the plastic component this was attributed to the presence of pre-existing fatigue microcracks preventing energy absorption by the formation of new microcracks. © 2014 Springer Science+Business Media. Source

Kidd L.J.,University of Queensland | Stephens A.S.,Griffith University | Kuliwaba J.S.,SA Pathology and Hanson Institute | Fazzalari N.L.,SA Pathology and Hanson Institute | And 2 more authors.
Bone | Year: 2010

Loading of the rat ulna is an ideal model to examine stress fracture healing. The aim of this study was to undertake a detailed examination of the histology, histomorphometry and gene expression of the healing and remodelling process initiated by fatigue loading of the rat ulna. Ulnae were harvested 1, 2, 4, 6, 8, and 10 weeks following creation of a stress fracture. Stress fracture healing involved direct remodelling that progressed along the fracture line as well as woven bone proliferation at the site of the fracture. Histomorphometry demonstrated rapid progression of basic multicellular units from 1 to 4 weeks with significant slowing down of healing by 10 weeks after loading. Quantitative PCR was performed at 4 hours, 24 hours, 4 days, 7 days, and 14 days after loading. Gene expression was compared to an unloaded control group. At 4 hours after fracture, there was a marked 220-fold increase (P < 0.0001) in expression of IL-6. There were also prominent peak increases in mRNA expression for OPG, COX-2, and VEGF (all P < 0.0001). At 24 hours, there was a peak increase in mRNA expression for IL-11 (73-fold increase, P < 0.0001). At 4 days, there was a significant increase in mRNA expression for Bcl-2, COX-1, IGF-1, OPN, and SDF-1. At 7 days, there was significantly increased mRNA expression of RANKL and OPN. Prominent, upregulation of COX-2, VEGF, OPG, SDF-1, BMP-2, and SOST prior to peak expression of RANKL indicates the importance of these factors in mediating directed remodelling of the fracture line. Dramatic, early upregulation of IL-6 and IL-11 demonstrate their central role in initiating signalling events for remodelling and stress fracture healing. © 2009 Elsevier Inc. All rights reserved. Source

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