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

Accelerating Medicines Partnership RA/SLE Network

doi:10.1038/s41467-024-52586-x

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

Accelerating Medicines Partnership RA/SLE Network

Medicine, Rheumatology Division

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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.

Original language	English (US)
Article number	9859
Journal	Nature communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-52586-x
State	Published - Dec 2024

Funding

The authors thank the Accelerating Medicines Partnership RA/SLE Network for the generation of the osteoarthritis and rheumatoid arthritis synovial scRNA-seq data. The authors thank Brigham and Women\u2019s Hospital (BWH) Center for Cellular Profiling: Cytometry and Single-Cell Multi-omics Core for assistance with cell sorting and single-cell transcriptomic data collection. We thank the Broad Genomics Platform for bulk sequencing services. The authors thank the Human Skin Disease Resource Center of Brigham and Women\u2019s Hospital which collected anonymous, discarded adult skin plus fat samples and provided them to our lab. The authors thank the Gift of Hope Organ & Tissue Donor Network, IL, as well as the donors\u2019 families, for the precious tissue samples. The authors thank Peter Nigrovic for serum derived from K/BxN mice. The authors thank the National Disease Research Interchange which collected post-mortem healthy synovial tissue. The authors thank the National Institutes of Arthritis and Musculoskeletal and Skin Diseases, T32AR007530-37, Immunologic Mechanisms and Rheumatic Disease (MBB), National Institutes of Arthritis and Musculoskeletal and Skin Diseases, P30 AR070253, Microgrant (HJF) and Arthritis National Research Foundation (HJF) for their generous funding. This work was supported by the Accelerating Medicines Partnership\u00AE Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP\u00AE RA/SLE) Network (AMP) in Rheumatoid Arthritis and Lupus Network. AMP is a public-private partnership (AbbVie Inc., Arthritis Foundation, Bristol-Myers Squibb Company, Foundation for the National Institutes of Health, GlaxoSmithKline, Janssen Research and Development, LLC, Lupus Foundation of America, Lupus Research Alliance, Merck & Co., Inc. Sharp & Dohme Corp., National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Pfizer Inc., Rheumatology Research Foundation, Sanofi and Takeda Pharmaceuticals International, Inc.) created to develop new ways of identifying and validating promising biological targets for diagnostics and drug development. Funding was provided through grants from the National Institutes of Health (UH2-AR067676, UH2-AR067677, UH2-AR067679, UH2-AR067681, UH2-AR067685, UH2- AR067688, UH2-AR067689, UH2-AR067690, UH2-AR067691, UH2-AR067694, and UM2- AR067678). The Human Skin Disease Resource Center of Brigham and Women\u2019s Hospital and Harvard Medical School collected anonymous, discarded adult skin plus fat samples removed as part of cosmetic surgery procedures and provided them to our lab. The Human Skin Disease Resource Center is supported in part by NIAMS Resource-based Center Grant # 1P30AR069625. This tissue was collected under IRB number 2020P003757. Abdominal adipose tissue was used to generate fat-conditioned media.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-024-52586-x

Cite this

@article{b7b57f9e040241e1859c7559e73bc5c2,

title = "Adipocyte associated glucocorticoid signaling regulates normal fibroblast function which is lost in inflammatory arthritis",

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.",

author = "{Accelerating Medicines Partnership RA/SLE Network} and Faust, {Heather J.} and Cheng, {Tan Yun} and Ilya Korsunsky and Watts, {Gerald F.M.} and Gal-Oz, {Shani T.} and Trim, {William V.} and Suppawat Kongthong and Jonsson, {Anna Helena} and Simmons, {Daimon P.} and Fan Zhang and Robert Padera and Susan Chubinskaya and Aaron Wyse and Andrew Cordle and Li, {Zhihan J.} and Zhu Zhu and Qian Xiao and Weisman, {Michael H.} and Dana Weisenfeld and Kathryn Weinand and Utz, {Paul J.} and Darren Tabechian and Melanie Smith and Kamil Slowikowski and Anvita Singaraju and Dagmar Scheel-Toellner and Seifert, {Jennifer A.} and Saori Sakaue and Ilfita Sahbudin and Laurie Rumker and Robinson, {William H.} and Felice Rivellese and Christopher Ritchlin and Yakir Reshef and Karim Raza and Javier Rangel-Moreno and Costantino Pitzalis and Harris Perlman and Orange, {Dana E.} and Alessandra Nerviani and Saba Nayar and Larry Moreland and Nghia Millard and Nida Meednu and Mears, {Joseph R.} and McGeachy, {Mandy J.} and Andrew McDavid and Mark Maybury and Marks, {Kathryne E.} and Mandelin, {Arthur M.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1038/s41467-024-52586-x",

language = "English (US)",

volume = "15",

journal = "Nature communications",

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AU - Accelerating Medicines Partnership RA/SLE Network

AU - Faust, Heather J.

AU - Cheng, Tan Yun

AU - Korsunsky, Ilya

AU - Watts, Gerald F.M.

AU - Gal-Oz, Shani T.

AU - Trim, William V.

AU - Kongthong, Suppawat

AU - Jonsson, Anna Helena

AU - Simmons, Daimon P.

AU - Zhang, Fan

AU - Padera, Robert

AU - Chubinskaya, Susan

AU - Wyse, Aaron

AU - Cordle, Andrew

AU - Li, Zhihan J.

AU - Zhu, Zhu

AU - Xiao, Qian

AU - Weisman, Michael H.

AU - Weisenfeld, Dana

AU - Weinand, Kathryn

AU - Utz, Paul J.

AU - Tabechian, Darren

AU - Smith, Melanie

AU - Slowikowski, Kamil

AU - Singaraju, Anvita

AU - Scheel-Toellner, Dagmar

AU - Seifert, Jennifer A.

AU - Sakaue, Saori

AU - Sahbudin, Ilfita

AU - Rumker, Laurie

AU - Robinson, William H.

AU - Rivellese, Felice

AU - Ritchlin, Christopher

AU - Reshef, Yakir

AU - Raza, Karim

AU - Rangel-Moreno, Javier

AU - Pitzalis, Costantino

AU - Perlman, Harris

AU - Orange, Dana E.

AU - Nerviani, Alessandra

AU - Nayar, Saba

AU - Moreland, Larry

AU - Millard, Nghia

AU - Meednu, Nida

AU - Mears, Joseph R.

AU - McGeachy, Mandy J.

AU - McDavid, Andrew

AU - Maybury, Mark

AU - Marks, Kathryne E.

AU - Mandelin, Arthur M.

PY - 2024/12

Y1 - 2024/12

N2 - 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.

AB - 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.

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JO - Nature communications

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M1 - 9859

ER -

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

Abstract

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