Validation of sex-dependent molecular pain mechanisms in OA

Through recent collaboration, three potential pathways were identified that might explain sexdependent differences in arthritis pain. These include: (i) 5 neurotrophins exclusively upregulated in female joints at the time of late OA pain behaviour (ii) evidence for increased complement pathway activation in female arthritis, and (iii) sex-dependent differences in the inflammatory cell profiles within the dorsal root ganglion. In this proposal we will explore these pathways in mice as they develop OA pain behaviour, and then test the sex-dependence and correlation with pain outcomes of candidate molecules in two large patient cohorts.

• Steer from the patient groups regarding the project approach and outcomes.
• Creation of an agreed molecular panel (46 genes) to test over the OA time course.
• Confirm regulation of identified neurotrophins in female compared with male mice exhibiting pain behaviour
• Determine the time course of this regulation with relation to development of pain and the tissue of origin
• Determine whether there are sex-dependent changes in complementthatalso associatewith pain
• Determine whether inflammatory changes (including complement) in DRG occur in surgically induced OA and whether these exhibit sex-dependence
• Determine whether moleculesvalidated in the mouseexhibit sex-dependence in human OA tissues from multiple highly phenotyped cohortsand how this relates to reported pain

Through the Centre for Osteoarthritis Pathogenesis Versus Arthritis regular “Research Showcase” days are being hold in which patients are being invited to hear about planned studies and to provide their feedback on (i) the importance of the study (ii) the proposed approach and (iii) how they think the results should be disseminated.