Identification of a synovial fluid protein as a putative driver of pain in osteoarthritis (OA)

PROJECT OVERVIEW

Pain remains the most important reason why patients with osteoarthritis (OA) attend health care professionals. The molecular drivers of pain in OA are likely to be multiple – driven by different tissue pathologies over the long course of their disease. One well validated pain target is nerve growth factor (NGF) which has proven validity in murine and human OA (1). Systemic factors are also likely to contribute to the pain experience and may account for chronic amplification of pain which occurs 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

1. Vincent TL. Peripheral Pain Mechanisms in Osteoarthritis. Pain. 2020;161(S138-S146,).

2. 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.

3. 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

Translational medicine, arthritis, systems biology, stem cell biology

CONTACT INFORMATION OF ALL SUPERVISORS

Tonia Vincent

Zameel Cader

Vicky Batchelor