Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease.

Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders (P = 2.4 × 10-22) and are associated with the polygenic diseases osteoporosis (P = 1.8 × 10-13) and osteoarthritis (P = 1.6 × 10-7). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease.

Acute exposure to prion infection induces transient oxidative stress progressing to be cumulatively deleterious with chronic propagation in vitro.

Neuronal loss is a pathological feature of prion diseases for which increased reactive oxygen species (ROS) and consequent oxidative stress is one proposed mechanism. The processes underlying ROS production in prion disease and the precise relationship to misfolding of the prion protein remain obscure. Using cell culture models of prion infection we found that cells demonstrate a rapid, prion protein (PrP) dependent, increase in intracellular ROS following exposure to infectious inoculum. ROS production correlated with internalisation and increased intracellular protease resistant PrP (PrP(Res)). The ROS increase was predominantly lysosomal in origin but not sustained, with cells adapting within 48 hours. Overall ROS levels remained normal in the chronically prion infected cell population; however a subpopulation characterised by loss of membrane phosphatidylserine asymmetry exhibited highly peroxidised intracellular aggregates that localised with PrP and intense caspase activation. These apoptotic cells showed increased ROS closely correlating with increased PrP(Res). Our findings demonstrate that a PrP-dependent, transient, increase in intracellular ROS is characteristic of acute cellular prion infection, while chronic phases of prion infection in vitro are associated with a significant subpopulation manifesting apoptosis accompanying heightened oxidative stress and increased PrP(Res) burden. Such observations strengthen the direct links between heightened ROS and ongoing prion propagation with eventual cellular demise.

Surveillance of Creutzfeldt-Jakob disease in Australia: 2008.

Australia-wide surveillance of all human transmissible spongiform encephalopathies (TSEs) is performed by the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR), since establishment in October 1993. During the surveillance period 1 April 2007 to 31 March 2008, the ANCJDR received 78 new suspect case notifications of TSEs (67 in 2007, 13 in 2008). This level of suspect case notification aligns with the previous 2006/2007 surveillance period, which was elevated in comparison to the previous 5 years. Based on the total number of probable and definite Creutzfeldt-Jakob disease (CJD) cases, encompassing retrospective cases to 1970 and prospectively ascertained cases from 1993 to 31 March 2008, the average age-adjusted mortality rate is 1.16 deaths per million per year. In this short report, we provide updated Australian TSE figures and describe recent changes in surveillance mechanisms and review their impact on case notifications and eventual CJD classification.