Identifying objective measures of sex-specific pain in humans that can be used diagnostically to target treatment.

Osteoarthritis, a painful disease that causes joint destruction, affects 530 million people worldwide and 10 million in the UK. No treatments stop osteoarthritis or manage pain. Pain reduces patient’s quality of life, causing immobility and isolation. Changes in bone structure in osteoarthritis correlate with pain severity, possibly because the bone contains many nerves.

Osteoarthritic pain affects nearly twice as many females than males, with pain being particularly common in post-menopause females. Females have higher osteoarthritis prevalence, clinical pain and inflammation than males, but molecular mechanisms explaining sex differences are lacking.

The main aims and objectives of the research study.

The pilot work shows that joint fluids from patients with knee osteoarthritis contain signals that affect nerve growth and function and that these signals correlate with indicators of bone changes.

The project aims to identify signals that drive pain and bone remodelling in human osteoarthritis and determine how these differ between males and females and pre and post menopause.

The objectives are:

1. To analyse stored synovial fluids from 41 female and 30 male osteoarthritis patients for signals that influence nerve invasion, bone changes and pain and combine it with the researchers’ existing data (31 males and 3 females) to determine sex-specific and menopause-specific differences in neuronal signals.
2. To apply joint fluids from osteoarthritic male, and pre- and post-menopausal females, onto the researchers’ human cell models of bone and nerve and measure responses.
3. To compare patient synovial fluid biomarker patterns with osteocyte and neuronal responses and identify sex specific mechanisms that link bone remodelling to pain.

How this research is going to help address MSK health.

The research will identify important mediators that drive pain processes and define the variability across male and female patients. The data will indicate which patients are predisposed to nerve growth, bone structural changes and therefore increased pain, and define how this varies between males and females, and post-menopause. This not only provides potential diagnostic biomarkers, but also mechanistic understanding, that could identify new interventions using drugs repurposed from osteoporosis or nervous system diseases such as epilepsy and migraine. The project will provide an objective measure of sex-specific pain that can be used diagnostically to tailor targeted treatments more appropriately to individual patients.

The main research methods, or datasets being used.

This project will use human osteoarthritic patients’ blood and joint fluids, with matched clinical and functional data, obtained by the Biomechanics and Bioengineering Research Centre Versus Arthritis.

Biochemical analysis using multiplex and targeted ELISAs will quantify the neuronal and bone remodelling proteins present in osteoarthritic joint fluids. Menopausal status will be determined by measuring Follicle Stimulating Hormone and oestrogen concentrations in matched blood samples.

Bone and nerve cell models will be used to define differences in response to joint fluids from males and females by comparing gene and protein expression, assessing nerve branching microscopically, and nerve function using calcium-imaging and micro electrode array analysis.

Sex-specific differences in neuronal factors will be determined using multivariate analysis including principal component analysis and multiple linear regression. Models will consider age, sex, weight, BMI, VAS score, KL grade and mediator concentration.

CASE STUDY 573

Cardiff University

Identifying objective measures of sex-specific pain in humans that can be used diagnostically to target treatment.

Researcher: Prof Deborah Mason.

University: Cardiff University.

Award stream: Inspiration Fund.

Award duration: 1 year.

Amount rewarded: £47,000.

Collaborations/ partners: Ryan Jones (University of Cardiff) and NHS Consultant Orthopaedic Surgeons Mr Chris Wilson, Mr Rhys Williams, and Mr Rhydian Morgan- Jones. The Biomechanics and Bioengineering Research Centre Versus Arthritis, Cardiff and Vale University Health Board (C&VUHB), and Cardiff and Vale Orthopaedic Centre (CAVOC). In kind support from bit.bio.