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Novel Receptor:Ligand Interactions in Osteolytic Diseases

Final Report Summary - NRLIOD (Novel Receptor:Ligand Interactions in Osteolytic Diseases)

Project context and objectives

The outgoing research objectives were to: (i) generate an OSCAR GFP-knockout mouse; (ii) learn the Collagen-Induced Arthritis (CIA) mouse mode; (iii) generate DAP12-/-OSCAR-/- mice and analyse their bone phenotype; and (iv) identify FcRgamma and DAP12-associated receptor: ligands. The training objectives were to: (a) learn knockout mouse technology; (b) breed OSCAR-/- mice with other knockout strains available, e.g. DAP12-/- mice, and learn bone histomorphometry; and (c) phenotype the knockout mice generated. Whilst the fellow was unsuccessful in generating an OSCAR GFP-knockout mouse, he generated an OSCAR knockout (OSCAR-/-) mouse and a panel of anti-mouse and anti-human OSCAR monoclonal antibody (mAb) reagents to identify OSCAR-expressing cells in vivo, in collaboration with Karsten Skjødt (Copenhagen, Denmark). He aimed to learn about the CIA mouse model. However, having discovered that our collaborators at the incoming host had successfully implemented the CIA model, the fellow learned about the mouse K/BxN serum arthritis model in the outgoing phase that has greater disease penetration.

Project outcomes

The K/BxN serum arthritis transfer model was successfully implemented in OSCAR-/- mice. Furthermore, the K/BxN serum arthritis model has a disease phenotype in OSCAR-/- mice, showing that OSCAR is required to suppress inflammation in arthritis in vivo, which is consistent with the new phenomenon of inhibitory ITAM signalling (Ivashkiv, L. B. European Journal of Immunology. 2011).

This knowledge will supplement ongoing arthritis models in Cambridge and Europe. The fellow successfully bred OSCAR-/- mice with DAP12-/- mice to generate DAP12-/-OSCAR-/- mice and analysed their bone phenotype; he used core facilities in the outgoing host to learn micro-cT and histomorphometry and transfer these skills back to Europe. It was realised during the project that collagen incorporated into the extracellular matrix is crucial for osteoclastogenesis in vivo. Thus the fellow established a successful European collaboration with Jean-Marie Delaisse and Thomas-Levin Andersen (Vejle, Denmark) to address this important aim. This research was published in the high-impact biomedical Journal of Clinical Investigation. The fellow was partially successful in identifying other FcRgamma and DAP12-associated receptor and ligands. Whilst he was unsuccessful in attempts to use blocking mAbs to identify other receptors, due to complications with isotype controls (likely due to Fc receptor binding that may explain the poor blocking activities achieved), he did discover a new OSCAR ligand - Surfactant Protein D (SP-D). The project then entered a new and exciting phase because SP-D is implicated in the pathogenesis of lung diseases, such as asthma, allergic rhinitis and lung cancer and has a protective role in rheumatoid arthritis (Christensen, A.F. et al. Arthritis Res Ther, 2010), which is consistent with the results of the K/BxN arthritis model in OSCAR-/- mice. The fellow built a website for Cambridge Immunology - see - that describes his research in detail and can be viewed by the public online.

Project results

Research methodology results:
(A) Established effective long-term European collaborators, such as Jean-Marie Delaisse (Vejle, Denmark) and Thomas-Levin Andersen (Vejle, Denmark), Karsten Skjødt (Copenhagen, Denmark) and Richard Farndale (Cambridge, UK) and international collaborators, such as Yongwon Choi (USA), Andrew Herr (USA), Hiroshi Takayanagi (Japan) and Marco Colonna (USA) who will enhance collaboration and European competitiveness.
(B) Learned about the K/BxN serum arthritis model that will transfer knowledge back to Europe and enhance European competitiveness.
(C) Identified a new OSCAR ligand, Surfactant Protein-D, that enhanced our molecular understanding of lung diseases and rheumatoid arthritis and facilitated the transfer of knowledge back to Europe, thereby increasing European competitiveness. In addition, the fellow learned about knockout mouse technology, bred OSCAR-/- mice on to mouse knockout strains in the Colonna lab., studied bone histomorphometry and micro-cT and phenotyped the bones of knockout mice.

The findings were published in the high-impact Journal of Clinical Investigation (Barrow et al., 2011). The fellow also developed his research on other immune molecules, such as SP-D, IL-34 (Wang at al., 2012) and LAIR-1 (Tang et al., 2012).

Socio-economic impacts

The fellow identified a novel pathway of osteoclastogenesis that is associated with post-menopausal osteoporosis (Kim et al. J Bone Miner Res, 2004) and is up-regulated in rheumatoid arthritis (Herman et al. Arthritis Rheum. 2008). We patented the work in the UK and it has now entered the international phase. Full licence was taken by Novo Nordisk, thus increasing European socio-economic impact and competitiveness. He also identified another ligand for OSCAR - SP-D. SP-D is genetically associated with various lung diseases and rheumatoid arthritis. This work could lead to the development of novel therapeutic reagents that could block OSCAR signalling in osteoclasts and treat diseases, such as osteoporosis, and suppress inflammation in lung disease and rheumatoid arthritis. Patients deficient in DAP12 suffer from a rare genetic disorder called Nasu-Hakola disease (NHD), also known as Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL), which is part of the Finnish disease heritage. The research on OSCAR may lead to molecular markers or cures for the osteoclast-mediated bone disease manifesting in NHD/PLOSL patients.