Projects per year
Our research programme focuses on understanding the molecular pathogenesis of chronic degenerative diseases such as osteoarthritis, with the goal of developing novel therapies to treat these conditions. We focus specifically on defining how the activity and availability of anabolic growth factors and metalloprotease inhibitors is regulated by their trafficking between pericellular heparan sulfate proteoglycans and the cell surface endocytic receptor LRP1.
(i) Defining molecular pathways that drive cartilage loss in osteoarthritis. Osteoarthritis is characterised by an increase in the activity of metalloproteases that degrade cartilage extracellular matrix components, and so impair the structural integrity of the tissue. This is caused by increased expression of these metalloproteases and decreased levels of their endogenous inhibitor, tissue inhibitor of metalloproteinases 3 (TIMP-3). Our group established that levels of TIMP-3 in cartilage are regulated by the equilibrium between its binding to heparan sulfate (HS) glycans in the extracellular matrix and its cellular endocytosis by the scavenger receptor, LDL receptor-related protein 1 (LRP1). Current projects focus on defining how HS sulfation patterns change tissue repair in OA, and designing small molecule inhibitors to target TIMP-3 loss as a therapy for osteoarthritis.
(ii) LRP1/HS axis also regulates macrophage behaviour. We found that LRP1 also dynamically regulates TIMP-3 levels in macrophages, where TIMP-3 is the primary inhibitor of TNF release by the metalloproteinase ADAM17. This enables LRP1 to control termination of TNF release during the inflammatory response. As in chondrocytes, macrophage HS protects TIMP-3 and other ligands from uptake by LRP1. We are examining changes in expression of HS biosynthesis enzymes and core proteins upon macrophage phenotype and activation, and looking at how this alters retention and biological activity of HS-binding cytokines, chemokines and growth factors during inflammation.
(iii) LRP1/HS in age-related macular degeneration (AMD). The LRP1/HS axis also regulates extracellular matrix turnover in the retina. Mutations in TIMP-3 cause Sorsby Fundus Dystrophy (SFD), a rare genetic form of macular degeneration that can serve as a model for the more common age-related macular degeneration. To better understand the molecular pathogenesis of AMD, we are investigating how retinal levels of wild-type and SFD mutants of TIMP-3 are regulated by LRP1 and HS.
Senior Fellow of Advance HE (2019-present)
Member of Versus Arthritis Musculoskeletal Disorders Research Advisory Group (2019-present)
Editorial board member, Journal of Biological Chemistry (2016-present)
Research Topic Editor, Frontiers in Immunology (2019)
Elected committee member of British Society for Matrix Biology (2014-2017)
University Research Lecturer, University of Oxford2012 → 2018
Career Development Fellow - Arthritis Research UK, University of Oxford2011 → 2016
Post-doctoral researcher, Imperial College London
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Treatment of osteoarthritis by inhibition of aggrecanases using targeted delivery of engineered TIMP-3
1/01/21 → 31/12/23
1/10/19 → 30/09/23
8/02/19 → 31/12/22
Does aberrant extracellular trafficking cause both age-related and genetic forms of macular degeneration?
1/10/21 → 30/09/24
1/07/19 → 25/08/19
Troeberg, L., Franchi, M., Masola, V. & Onisto, M., 19 Feb 2021, (E-pub ahead of print) In: FEBS Journal.
Research output: Contribution to journal › Article › peer-review12 Citations (Scopus)
McClurg, O., Tinson, R. & Troeberg, L., 5 Feb 2021, In: Pharmaceuticals. 14, 2, 126.
Research output: Contribution to journal › Article › peer-reviewOpen AccessFile1 Citation (Scopus)4 Downloads (Pure)
Troeberg, L., Lord, M. S. & Petrey, A. C., 15 Oct 2020, In: Frontiers in Immunology. 11, 595867.
Research output: Contribution to journal › Editorial › peer-reviewOpen AccessFile3 Downloads (Pure)
Interleukin 13 (IL-13)-regulated expression of the chondroprotective metalloproteinase ADAM15 is reduced in aging cartilageYang, C. Y., Chanalaris, A., Bonelli, S., McClurg, O., Hiles, G. L., Cates, A. L., Zarebska, J. M., Vincent, T. L., Day, M. L., Müller, S. A., Lichtenthaler, S. F., Nagase, H., Scilabra, S. D. & Troeberg, L., Dec 2020, In: Osteoarthritis and Cartilage Open. 2, 4, 100128.
Research output: Contribution to journal › Article › peer-reviewOpen AccessFile4 Downloads (Pure)
Quantitative Mass Spectrometry-Based Secretome Analysis as a Tool to Investigate Metalloprotease and TIMP ActivityYang, C-Y., Troeberg, L. & Scilabra, S. D., 2020, ADAMTS Proteases. Apte, S. S. (ed.). Springer, Vol. 2043. p. 265-273 9 p. (Methods in Molecular Biology).
Research output: Chapter in Book/Report/Conference proceeding › Chapter (peer-reviewed) › peer-review
Troeberg, Linda (Recipient), 2011
Prize: Fellowship awarded competitively