Obesity defined molecular endotypes in the synovium of patients with osteoarthritis provides a rationale for therapeutic targeting of fibroblast subsets

This study aimed to establish molecular endotypes in osteoarthritis soft joint tissue driven by obesity in both load-bearing and non-load bearing joints. Transcriptomic analysis found the inflammatory landscape of OA synovial fibroblasts (SF) are independently impacted by obesity, joint loading, and anatomical site with significant heterogeneity between obese and normal weight patients. These findings demonstrate the significance of obesity in changing the inflammatory landscape of synovial fibroblasts in both load bearing and non-load bearing joints. The molecular endotypes identified may provide a route for the stratification of patients in clinical trials, providing a rational for the therapeutic targeting of specific SF subsets in specific patient populations with arthritic conditions. Overall design: Hand, hip, knee, and foot joint synovial tissue were collected peri-operatively from osteoarthritis patients (n=24) classified as obese (BMI > 30) or normal weight (BMI 18.5-24.9). Each joint sample collected was from an independent patient undergoing arthroscopy at a single anatomical joint. Total RNA was extracted using Qiagen's RNeasy Mini Kit, following manufacturer's instructions for on column DNase treatment. Library preparation and RNA-sequencing was performed by Genomics Facility at University of Birmingham using Lexogen QuantSeq 3' kit and sequenced on Illumina's NextSeq 500. The sequence reads quality checks were carried out using fastQC, following which the bbduk from BBMap (version 38.87) software was used to trim Illumina adapters and polyA tails. Reads were mapped to hg38 reference human genome using Star Aligner. The R package DESeq2 was used to normalise raw read counts and perform statistical comparisons using VST transformations.