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NDORMS DPhil & MSc by Research

PROJECT OVERVIEW

Systemic and focal bone loss is a common feature of many forms of arthritis. However inappropriate new bone formation also occurs in inflammatory arthritides including ankylosing spondylitis (AS), osteoarthritis (OA), psoriatic arthritis and even in rheumatoid arthritis (RA). So how does inflammation lead to new bone formation and ankyloses? These features are regarded as critical parameters of the structural damage in AS, occurring preferentially in the spine and pelvis but also in the periphery at the bone insertion of tendons and ligaments (enthesis). In general, inflammation is thought to inhibit bone forming osteoblasts. So what is different about AS? How does inflammation trigger new bone formation? Is it a disproportionate tissue repair response induced by inflammation - a failure to turn off new bone formation or exaggerated repair in excess of bone catabolism?

Monocyte/macrophages are crucial for tissue repair and regeneration but can also contribute to tissue damage and fibrosis. We have demonstrated that the interaction between mesenchymal stem cells and monocytes leads to the activation of STAT3 and drives osteoblast generation (1). In AS, differential patterns of monocyte activation have been reported (2). Macrophage polarisation, as assessed by the expression of IRF5 and differential cytokine production, correlates disease severity in both acute and chronic inflammation (3, 4). This project is aimed at investigating the contribution of inflammatory and tissue resident macrophages to bone formation in a murine model of AS (5). The findings from this research will underpin novel therapies to tackle the problem of inappropriate bone formation - a primary cause of morbidity in AS.

TRAINING OPPORTUNITIES

The Kennedy Institute is a world-renowned research centre and is housed in a brand new state-of-the-art research facility. Full training will be provided in a range of cell and molecular biology techniques as well as in vivo disease models. Students will receive specialist training on state of the art in vivo imaging technologies; IVIS and microCt. A core curriculum of 20 lectures will be taken in the first term of year 1 to provide a solid foundation in musculoskeletal sciences, immunology and data analysis. Students will attend weekly departmental meetings and will be expected to attend seminars within the department and those relevant in the wider University. Subject-specific training will be received through our group's weekly supervision meetings. Students will also attend external scientific conferences where they will be expected to present the research findings.

RELEVANT PUBLICATIONS

  1. Nicolaidou V, et al. Monocytes induce STAT3 activation in human mesenchymal stem cells to promote osteoblast formation. PLoS One2012;7(7):e39871. 
  2. Wright C, et al. Ankylosing spondylitis monocytes show upregulation of proteins involved in inflammation and the ubiquitin proteasome pathway. Ann Rheum Dis2009 Oct;68(10):1626-32. 
  3. Weiss M, et al. IRF5 controls both acute and chronic inflammation. PNAS 2015 Sep 1;112(35):11001-6 
  4. Krausgruber T, et al. IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat Immunol. 2011 Mar;12(3):231-8 
  5. Ruutu M, et al. beta-glucan triggers spondylarthritis and Crohn's disease-like ileitis in SKG mice. Arthritis Rheum2012 Jul;64(7):2211-22.

FURTHER INFORMATION

Prof Nikki Horwood, Kennedy Institute, University of Oxford
nicole.horwood@kennedy.ox.ac.uk

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