Background: Synovial inflammation is associated with pain severity in patients with knee osteoarthritis (OA). The aim here was to determine in a population with knee OA, whether synovial tissue from patient-reported sites associated with pain exhibited different synovial fibroblast transcriptomes, compared to synovial tissue from patient-matched non-painful sites. A further aim was to compare differences between early and end-stage disease synovial fibroblasts.

Methods: Patients undergoing arthroscopy or total joint replacement, categorised as early knee OA (n=30) and end-stage knee OA (n=41) respectively, were recruited. Patient reported pain was recorded using EQ5D, Oxford Knee Score (OKS), Visual Analogue Scale (VAS) questionnaires and using an anatomical knee pain map where patient marked painful and non-painful sites. Proton density fat suppressed MRI axial and sagittal sequences were analysed and scored for synovitis. Synovial tissue was obtained from the medial and lateral parapatellar and suprapatellar sites. RNA sequencing was performed using Illumina’s NextSeq 500 (GSE176223) and single-RNA seq performed using 10x (GSE176308). Transcriptomes were functionally characterised using Ingenuity Pathway Analysis.

Findings: Parapatellar synovitis was significantly associated with increased OA pain perception. Functional pathway analysis revealed that early OA painful sites mediate immune cell recruitment and promote the formation and development of neurites.

Conclusion: OA disease progression and the presence of pain in early OA is associated with different synovial pathotypes. Further interrogation of these pathotypes will increase our understanding of the role of synovitis in OA joint pain and provide a rationale for the therapeutic targeting to alleviate pain in patients.

Full study details can be found in our publication DOI: 10.1016/j.ebiom.2021.103618 (PMID: 34628351 PMCID: PMC8511845)

On going:

• integrating proteomic data from synovial tissues and matched synovial fluids to further investigate the underlying cellular mechanisms between synovial fibroblasts and neurones that mediate nociceptor activity
• testing antisense oligonucleotides (ASOs) designed to silence candidate genes and their efficacy in modulating the fibroblast pain pathotype and reducing the growth and sensory function of neurons
• intra-articular delivery of ASO into the synovial joint tissues and its analgesic efficacy in an experimental model of OA pain will be evaluated