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Adipocyte associated glucocorticoid signaling regulates normal fibroblast function which is lost in inflammatory arthritis [adipose_scRNAseq]

ABSTRACT: Fibroblasts play critical roles in tissue homeostasis, but in pathologic states can drive fibrosis, inflammation, and tissue destruction. In the joint synovium, fibroblasts provide homeostatic maintenance and lubrication. Little is known about what regulates the homeostatic functions of fibroblasts in healthy conditions. We performed RNA sequencing of healthy human synovial tissue and identified a fibroblast gene expression program characterized by enhanced fatty acid metabolism and lipid transport. We found that fat-conditioned media reproduces key aspects of the lipid-related gene signature in cultured fibroblasts. Fractionation and mass spectrometry identified cortisol in driving the healthy fibroblast phenotype, confirmed using glucocorticoid receptor gene (NR3C1) deleted cells. Depletion of synovial adipocytes in mice resulted in loss of the healthy fibroblast phenotype and revealed adipocytes as a major contributor to active cortisol generation via Hsd11β1 expression. Cortisol signaling in fibroblasts mitigated matrix remodeling induced by TNFα- and TGFβ, while stimulation with these cytokines repressed cortisol signaling and adipogenesis. Together, these findings demonstrate the importance of adipocytes and cortisol signaling in driving the healthy synovial fibroblast state that is lost in disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE233500 | GEO | 2024/08/08

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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Adipocyte associated glucocorticoid signaling regulates normal fibroblast function which is lost in inflammatory arthritis [adipose_scRNAseq]

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