Preservation of bone mass is crucial for healthy ageing and largely depends on adequate responses of matrix-embedded osteocytes. These cells control bone formation and resorption concurrently by secreting the WNT/-catenin antagonist sclerostin (SOST). Osteocytes reside within a low oxygen microenvironment, but whether and how oxygen sensing regulates their function remains elusive. Here, we show that conditional deletion of the oxygen sensor prolyl hydroxylase (PHD) 2 in osteocytes results in a high bone mass phenotype, which is caused by increased bone formation and decreased resorption. Mechanistically, enhanced HIF-1 signalling increases Sirtuin 1-dependent deacetylation of the Sost promoter, resulting in decreased sclerostin expression and enhanced WNT/-catenin signalling. Additionally, genetic ablation of PHD2 in osteocytes blunts osteoporotic bone loss induced by estrogen deficiency or mechanical unloading. Thus, oxygen sensing by PHD2 in osteocytes negatively regulates bone mass through epigenetic regulation of sclerostin and targeting PHD2 elicits an osteo-anabolic response in osteoporotic models. ; Research Foundation – Flanders (FWO: G.0A72.13, G.096414 and G0A4216N) and P.C. from long-term structural funding – Methusalem Funding by the Flemish Government.
Brexit and the troubled state of the NHS call for re-thinking the UK's approach to health. The EU referendum vote reveals deep social divisions as well as presenting the country with important decisions and negotiations about the future. At the same time, health problems are growing; the NHS faces severe financial constraints and appears to lurch from crisis to crisis, with leaving the European Union likely to exacerbate many problems including staffing issues across the whole sector. However, new scientific developments and digital technology offer societies everywhere massive and unprecedented opportunities for improving health. It is vital for the country that the NHS is able to adopt these discoveries and see them translated into improved patient care and population health, but also that the UK benefits from its capabilities and strengths in these areas.
Fully activated innate immune cells are required for effective responses to infection, but their prompt deactivation and removal are essential for limiting tissue damage. Here, we have identified a critical role for the prolyl hydroxylase enzyme Phd2 in maintaining the balance between appropriate, predominantly neutrophil-mediated pathogen clearance and resolution of the innate immune response. We demonstrate that myeloid-specific loss of Phd2 resulted in an exaggerated inflammatory response to Streptococcus pneumonia, with increases in neutrophil motility, functional capacity, and survival. These enhanced neutrophil responses were dependent upon increases in glycolytic flux and glycogen stores. Systemic administration of a HIF-prolyl hydroxylase inhibitor replicated the Phd2-deficient phenotype of delayed inflammation resolution. Together, these data identify Phd2 as the dominant HIF-hydroxylase in neutrophils under normoxic conditions and link intrinsic regulation of glycolysis and glycogen stores to the resolution of neutrophil-mediated inflammatory responses. These results demonstrate the therapeutic potential of targeting metabolic pathways in the treatment of inflammatory disease. ; This work was principally supported by a Wellcome Trust Senior Clinical Fellowship award (098516 to SRW), Medical Research Council (MRC) Clinical Training Fellowship awards (G0802255 to AART; MR/K023845/1 to RSD), an Academy of Medical Sciences (AMS) starter grant (to AART), a Wellcome Trust Senior Clinical Fellowship award (076945 to DHD), British Lung Foundation Fellowship (F05/7 to HMM), and a Engineering and Physical Sciences Research Council and Medical Research Council grant (EP/L016559/1, JAW). The MRC /University of Edinburgh Centre for Inflammation Research is supported by an MRC Centre Grant. The work of PC is supported by long-term structural funding-Methusalem funding from the Flemish Government. CJS thanks the Wellcome Trust and Cancer Research UK for support.
Understanding SARS-CoV-2 transmission in higher education settings is important to limit spread between students, and into at-risk populations. In this study, we sequenced 482 SARS-CoV-2 isolates from the University of Cambridge from 5 October to 6 December 2020. We perform a detailed phylogenetic comparison with 972 isolates from the surrounding community, complemented with epidemiological and contact tracing data, to determine transmission dynamics. We observe limited viral introductions into the university; the majority of student cases were linked to a single genetic cluster, likely following social gatherings at a venue outside the university. We identify considerable onward transmission associated with student accommodation and courses; this was effectively contained using local infection control measures and following a national lockdown. Transmission clusters were largely segregated within the university or the community. Our study highlights key determinants of SARS-CoV-2 transmission and effective interventions in a higher education setting that will inform public health policy during pandemics. ; DA is a Wellcome Clinical PhD Fellow and gratefully supported by the Wellcome Trust (Grant number: 222903/Z/21/Z). BW receives funding from the University of Cambridge and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC) at the Cambridge University Hospitals NHS Foundation Trust. IG is a Wellcome Senior Fellow and is supported by the Wellcome Trust (Grant number: 207498/Z/17/Z and 206298/B/17/Z). EMH is supported by a UK Research and Innovation (UKRI) Fellowship: MR/S00291X/1. CJRI acknowledges Medical Research Council (MRC) funding (ref: MC_UU_00002/11). NJM is supported by the MRC (CSF MR/P008801/1) and NHSBT (WPA15-02). AJP gratefully acknowledge the support of the Biotechnology and Biological Sciences Research Council (BBSRC); their research was funded by the BBSRC Institute Strategic Programme Microbes in the Food Chain BB/R012504/1 and its constituent project BBS/E/F/000PR10352, also Quadram Institute Bioscience BBSRC funded Core Capability Grant (project number BB/CCG1860/1). LdP and OGP were supported by the Oxford Martin School. This research was supported by the NIHR Cambridge BRC. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. The COVID-19 Genomics UK Consortium is supported by funding from the MRC part of UK Research & Innovation (UKRI), the National Institute of Health Research and Genome Research Limited, operating as the Wellcome Sanger Institute. The Cambridge Covid-19 testing Centre is funded by the Department of Health and Social Care, UK Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. For the purpose of Open Access, the author has applied a CC-BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
Understanding SARS-CoV-2 transmission in higher education settings is important to limit spread between students, and into at-risk populations. In this study, we sequenced 482 SARS-CoV-2 isolates from the University of Cambridge from 5 October to 6 December 2020. We perform a detailed phylogenetic comparison with 972 isolates from the surrounding community, complemented with epidemiological and contact tracing data, to determine transmission dynamics. We observe limited viral introductions into the university; the majority of student cases were linked to a single genetic cluster, likely following social gatherings at a venue outside the university. We identify considerable onward transmission associated with student accommodation and courses; this was effectively contained using local infection control measures and following a national lockdown. Transmission clusters were largely segregated within the university or the community. Our study highlights key determinants of SARS-CoV-2 transmission and effective interventions in a higher education setting that will inform public health policy during pandemics. ; DA is a Wellcome Clinical PhD Fellow and gratefully supported by the Wellcome Trust (Grant number: 222903/Z/21/Z). BW receives funding from the University of Cambridge and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC) at the Cambridge University Hospitals NHS Foundation Trust. IG is a Wellcome Senior Fellow and is supported by the Wellcome Trust (Grant number: 207498/Z/17/Z and 206298/B/17/Z). EMH is supported by a UK Research and Innovation (UKRI) Fellowship: MR/S00291X/1. CJRI acknowledges Medical Research Council (MRC) funding (ref: MC_UU_00002/11). NJM is supported by the MRC (CSF MR/P008801/1) and NHSBT (WPA15-02). AJP gratefully acknowledge the support of the Biotechnology and Biological Sciences Research Council (BBSRC); their research was funded by the BBSRC Institute Strategic Programme Microbes in the Food Chain BB/R012504/1 and its constituent project BBS/E/F/000PR10352, also Quadram Institute Bioscience BBSRC funded Core Capability Grant (project number BB/CCG1860/1). LdP and OGP were supported by the Oxford Martin School. This research was supported by the NIHR Cambridge BRC. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. The COVID-19 Genomics UK Consortium is supported by funding from the MRC part of UK Research & Innovation (UKRI), the National Institute of Health Research and Genome Research Limited, operating as the Wellcome Sanger Institute. The Cambridge Covid-19 testing Centre is funded by the Department of Health and Social Care, UK Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. For the purpose of Open Access, the author has applied a CC-BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
