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Synovial fibroblasts from obese hip osteoarthritis patients exhibit distinct single-cell subsets characterised by pathological inflammatory functions

ABSTRACT: Inflammation of synovial tissue (synovitis) is a hallmark of osteoarthritis (OA) pathogenesis and is pronounced in obese individuals. The aim of this study was therefore to perform scRNA-seq analysis of synovial fibroblast from hip OA patients who were either obese or normal-weight to identify specific fibroblast subsets that exhibit disease-associated inflammatory functions. : scRNA-seq identified eight OA synovial fibroblast clusters, with distinct differences between obese and normal-weight patients. Fibroblast clusters in obese OA patients highly expressed gene signatures related to immune cell regulation, fibrosis and inflammatory signalling, including Chitinase3-like 1 (CHI3L1), CXCL12, osteonectin (SPARC), SMOC2 and Galectin-1 (LGALS1). Pseudotemporal expression dynamics demonstrated a transition in the expression of the transcriptional regulator MYC and Inhibin A in normal-weight clusters, and the expression of FOS and CHI3L1 in obese fibroblast clusters. Analysis of fibroblast conditioned media showed that obese OA fibroblasts secreted significantly greater amounts of CHI3L1, whilst normal-weight fibroblasts secreted greater amounts of Inhibin.

ORGANISM(S): Homo sapiens

PROVIDER: GSE152815 | GEO | 2020/10/31

REPOSITORIES: GEO

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Project description:Synovial fibroblasts in persistent inflammatory arthritis have been suggested to have parallels with cancer growth and wound healing, both of which involve a stereotypical serum response program. We tested the hypothesis that a serum response program can be used to classify diseased tissues, and investigated the serum response program in fibroblasts from multiple anatomical sites and two diseases. To test our hypothesis we utilized a bioinformatics approach to explore a publicly available microarray dataset including RA, OA and normal synovial tissue, then extended those findings in a new microarray dataset representing matched synovial, bone marrow and skin fibroblasts cultured from RA and OA patients undergoing arthroplasty. The classical fibroblast serum response program discretely classified RA, OA and normal synovial tissues. Analysis of low and high serum treated fibroblast microarray data revealed a hierarchy of control, with anatomical site the most powerful classifier followed by response to serum and then disease. In contrast to skin and bone marrow fibroblasts, exposure of synovial fibroblasts to serum led to convergence of RA and OA expression profiles. Pathway analysis revealed three inter-linked gene networks characterising OA synovial fibroblasts: Cell remodelling through insulin-like growth factors, differentiation and angiogenesis through ?3 integrin, and regulation of apoptosis through CD44. We have demonstrated that Fibroblast serum response signatures define disease at the tissue level, and that an OA specific, serum dependent repression of genes involved in cell adhesion, extracellular matrix remodelling and apoptosis is a critical discriminator between cultured OA and RA synovial fibroblasts. Fibroblasts were isolated from synovium, bone marrow and skin tissue samples taken at the time of knee or hip replacement surgery from 12 rheumatoid arthritis patients meeting the 1987 ACR criteria and 6 osteoarthritis patients diagnosed on the basis of characteristic x-ray findings and the absence of features suggestive of inflammatory arthritis. Only one hip sample was present in either disease group. Fibroblasts were maintained in fibroblast medium (consisting of 81.3% RPMI 1640, 10% FCS, 0.81x MEM non-essential amino acids, 0.81mM sodium orthopyruvate, 1.62mM glutamine, 810U/ml penicillin and 81?g/ml streptomycin) at 37°C in a humidified 5% CO2 atmosphere.

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Synovial fibroblasts from obese hip osteoarthritis patients exhibit distinct single-cell subsets characterised by pathological inflammatory functions

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