Distinct fibroblast subsets drive inflammation and damage in arthritis
Open accessAbstract
The identification of lymphocyte subsets with non-overlapping effector functions has been pivotal to the development of targeted therapies in immune-mediated inflammatory diseases (IMIDs)1,2. However, it remains unclear whether fibroblast subclasses with non-overlapping functions also exist and are responsible for the wide variety of tissue-driven processes observed in IMIDs, such as inflammation and damage 3-5. Here we identify and describe the biology of distinct subsets of fibroblasts responsible for mediating either inflammation or tissue damage in arthritis. We show that deletion of fibroblast activation protein-α (FAPα)+ fibroblasts suppressed both inflammation and bone erosions in mouse models of resolving and persistent arthritis. Single-cell transcriptional analysis identified two distinct fibroblast subsets within the FAPα+ population: FAPα+THY1+ immune effector fibroblasts located in the synovial sub-lining, and FAPα+THY1- destructive fibroblasts restricted to the synovial lining layer. When adoptively transferred into the joint, FAPα+THY1- fibroblasts selectively mediate bone and cartilage damage with little effect on inflammation, whereas transfer of FAPα+ THY1+ fibroblasts resulted in a more severe and persistent inflammatory arthritis, with minimal effect on bone and cartilage. Our findings describing anatomically discrete, functionally distinct fibroblast subsets with non-overlapping functions have important implications for cell-based therapies aimed at modulating inflammation and tissue damage.
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Single-cell sequencing indicates common traits are preserved across tissues and species.
“While single-cell sequencing indicates common traits are preserved49–51, it will become increasingly pressing to define common and specific effects of CAFs.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [50]
The paper’s discussion of homologous fibroblast subsets (indexed under Abstract; page unavailable) reports shared gene-expression profiles in human and mouse arthritic synovium, supporting preservation across species. It does not establish that those traits are preserved across different tissues; both datasets concern synovium. (LLM, conf=0.88)
Experimental — accuracy not yet measuredOverwhelming evidence points to a degree of specialization among CAFs, which may reflect the increasingly appreciated specialization of normal fibroblasts.
“Overwhelming evidence now points to a degree of specialization among CAFs, which may reflect the increasingly appreciated specialization of normal fibroblasts19,50.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [50]
A range of mesenchymal progenitor cells are implicated in the initiation and propagation of fibrosis.
“Recent studies have implicated a range of mesenchymal progenitor cells (MPs) in the initiation and propagation of fibrosis28–30.”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [28]
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- Authors
- Croft, A. P., Campos, J., Jansen, K., Turner, J. D., Marshall, J., Attar, M., Savary, L., Wehmeyer, C., Naylor, A. J., Kemble, S., Begum, J., Dürholz, K., Perlman, H., Barone, F., McGettrick, H. M., Fearon, D. T., Wei, K., Raychaudhuri, S., Korsunsky, I., Brenner, M. B., Coles, M., Sansom, S. N., Filer, A., & Buckley, C. D.
- Affiliations
- Queen Elizabeth Hospital Birmingham (GB)
- University of Oxford (GB)
- University of Münster (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Northwestern University (US)
- Cold Spring Harbor Laboratory (US)
- Brigham and Women's Hospital (US)
- University Hospitals Birmingham NHS Foundation Trust (GB)
- Corresponding author
- Buckley, Christopher D.
- ORCID
- Croft, Adam P.
- Campos, Joana
- Jansen, Kathrin
- Turner, Jason D.
- Marshall, Jennifer
- Attar, Moustafa
- Wehmeyer, Corinna
- Naylor, Amy J.
- Kemble, Samuel
- Begum, Jenefa
- Perlman, Harris
- Barone, Francesca
- McGettrick, Helen M.
- Fearon, Douglas T.
- Wei, Kevin
- Raychaudhuri, Soumya
- Korsunsky, Ilya
- Brenner, Michael B.
- Coles, Mark
- Sansom, Stephen N.
- Filer, Andrew
- Buckley, Christopher D.
- Venue
- Nature
- Published
- 2019-05-29
- Volume
- 570
- Issue
- 7760
- Pages
- 246-251
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6690841
- OpenAlex
- W2944564829
- Cited by
- 976
- References
- 28
- Citations by year
- 2026: 147 · 2025: 144 · 2024: 137 · 2023: 134 · 2022: 128 · 2021: 153 · 2020: 94 · 2019: 36 · 2013: 1 · 2012: 1
- FWCI
- 78.26
- Type
- journal article
- Language
- en
- Update notices
- correction (2025-12-12)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (WT104551MA)
- Kennedy Trust for Rheumatology Research (KENN161701, KENN161703)
- National Institute for Health and Care Research (bircrf-2012-1, NF-SI-0617-10128, CL-2018-09-001)
- Academy of Medical Sciences (SGL021\1029)
- Versus Arthritis (19791, 21743, 20015, 14476, 19899, 18547, 21236)
- National Institutes of Health (5r01ar063759-07)
- Medical Research Council (MR/S025308/1, MR/N026977/1)
- National Heart, Lung, and Blood Institute (R01HL134375)
- National Human Genome Research Institute (U01HG009379)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (UH2AR067677, R01-AR063759)
- Topics
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
- Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
- Keywords
- arthritis, fibroblast activation protein, CD90, synovial lining, bone erosion, cartilage damage, joint inflammation, tissue damage, adoptive transfer, immune-mediated inflammatory diseases
- MeSH terms
- RNA-Seq, Fibroblast Activation Protein Alpha, Animals, Arthritis, Rheumatoid, Bone and Bones, Female, Fibroblasts, Humans, Inflammation, Joints, Male, Membrane Proteins, Endopeptidases, Serine Endopeptidases, Synovial Membrane, Gelatinases, Thy-1 Antigens, Mice, Single-Cell Analysis
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