in long standing disease and is more common in women than men.
We have observed that the synovial fluid taken from patients with OA is able to simulate firing of induced pluripotent stem cell (iPSC)-derived sensory neurons. We have established that this is true for male and female synovial fluid and is unlikely to be due to NGF, as these cells are “non-peptidergic” (2) and do not have the high affinity NGF receptor, nor do they respond to stimulation with recombinant NGF. Partial characterisation of the synovial fluid suggests that the activity is contained within a high molecular weight fraction (>100kDa). This is interesting because most neuronal sensitisers (cytokines, kinins, neurotrophic factors) are typically <50kDa. A number of putative molecules that could account for this activity and which are associated with patient reported pain have been identified through STEpUP OA, the largest proteomic analysis of synovial fluid in OA to date (3). This cohort contains data on over 1300 individual synovial fluid samples taken from patients with established OA. For each individual there are demographic (sex, age, weight/body mass index) and clinical outcome measures (pain, Xray scores).
The aims of this project is to identify the high MW synovial fluid protein that mediates sensory nerve sensitisation and determine (i) where it is being generated (this could be from a joint tissue or from the systemic circulation), (ii) how this molecule correlates with reported pain in OA male and female subjects using STEpUP OA data, (iii) consider ways to neutralise it in order to understand its potential therapeutic importance.
KEYWORDS:
Pain, osteoarthritis (OA), iPSCs, proteomics, synovial fluid
TRAINING OPPORTUNITIES:
- Purification and characterisation of protein activity using protein biochemistry techniques
- Proteomic analysis of an existing resource (STEpUP OA) that combines molecular and clinical data
- Differentiation, culture and maintenance of iPSC-derived sensory neurons
- Neurobiological techniques for assessing nerve activity
- Advanced imaging techniques used to visualise sensory neuron activity and remodelling in osteoarthritic models
KEY PUBLICATIONS:
- Vincent TL. Peripheral Pain Mechanisms in Osteoarthritis. Pain. 2020;161(S138-S146,).
- Volpato V, Smith J, Sandor C, Ried JS, Baud A, Handel A, et al. Reproducibility of Molecular Phenotypes after Long-Term Differentiation to Human iPSC-Derived Neurons: A Multi-Site Omics Study. Stem Cell Reports. 2018;11(4):897–911.
- Perry TA, Deng Y, Hulley PA, Maciewicz RA, Mitchelmore J, Larsson S, et al. Large-scale molecular endotype discovery in synovial fluid reveals osteoarthritis as a single biological continuum. Nat Commun. 2026;17;4721 (2026). https://doi.org/10.1038/s41467-026-71632-4(1).
THEMES: (4 key themes)
Translational medicine, arthritis, systems biology, stem cell biology
CONTACT INFORMATION OF ALL SUPERVISORS:
- Lead Supervisor: Tonia Vincent Tonia.vincent@kennedy.ox.ac.uk
- Supervisory team: Zam Cader zameel.cader@ndcn.ox.ac.uk
- Postdoc Supervisor: Vicky Batchelor Vicky.batchelor@kennedy.ox.ac.uk
PROJECT CODE: KIR-NC-12
