1. Adipocyte associated glucocorticoid signaling regulates normal fibroblast function which is lost in inflammatory arthritis.
- Author
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Faust HJ, Cheng TY, Korsunsky I, Watts GFM, Gal-Oz ST, Trim WV, Kongthong S, Jonsson AH, Simmons DP, Zhang F, Padera R, Chubinskaya S, Wei K, Raychaudhuri S, Lynch L, Moody DB, and Brenner MB
- Subjects
- Animals, Mice, Humans, Adipogenesis genetics, 11-beta-Hydroxysteroid Dehydrogenase Type 1 metabolism, 11-beta-Hydroxysteroid Dehydrogenase Type 1 genetics, Mice, Inbred C57BL, Mice, Knockout, Male, Transforming Growth Factor beta1 metabolism, Arthritis metabolism, Arthritis genetics, Arthritis pathology, Tumor Necrosis Factor-alpha metabolism, Fibroblasts metabolism, Adipocytes metabolism, Signal Transduction, Receptors, Glucocorticoid metabolism, Receptors, Glucocorticoid genetics, Synovial Membrane metabolism, Synovial Membrane pathology, Hydrocortisone metabolism, Glucocorticoids metabolism
- Abstract
Fibroblasts play critical roles in tissue homeostasis, but in pathologic states they can drive fibrosis, inflammation, and tissue destruction. Little is known about what regulates the homeostatic functions of fibroblasts. Here, we perform RNA sequencing and identify a gene expression program in healthy synovial fibroblasts characterized by enhanced fatty acid metabolism and lipid transport. We identify cortisol as the key driver of the healthy fibroblast phenotype and that depletion of adipocytes, which express high levels of Hsd11b1, results in loss of the healthy fibroblast phenotype in mouse synovium. Additionally, fibroblast-specific glucocorticoid receptor Nr3c1 deletion in vivo leads to worsened arthritis. Cortisol signaling in fibroblasts mitigates matrix remodeling induced by TNF and TGF-β1 in vitro, while stimulation with these cytokines represses 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., Competing Interests: Competing interests M.B.B. serves on the scientific advisory board for GlaxoSmithKline and as a consultant for Moderna and 4FO ventures. Consulting relates to programs specific to each company and does not directly relate to the research in this report. MBB is the founder of Mestag Therapeutics which is focused on fibroblast-mediated pathology but not directly related to the research in this report. The remaining authors declare no competing interests., (© 2024. The Author(s).)
- Published
- 2024
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