Spatial patterning of fibroblast TGFβ signaling underlies treatment resistance in rheumatoid arthritis
Treatment-refractory rheumatoid arthritis (RA) is a major unmet need, and the underlying mechanisms are poorly understood. To identify molecular determinants of refractory RA, we performed spatial transcriptomic profiling on synovial tissue biopsy samples taken 6 months before and after treatment. In the baseline biopsy samples of non-remitting patients, we identified increased fibrogenic signaling within vascular tissue niches, marked by high fibroblast COMP expression. We uncovered a role of endothelial-derived Notch signaling as an upstream regulator of fibroblast transforming growth factor beta (TGFβ) signaling via its opposing ability to induce TGFβ isoform expression while suppressing TGFβ receptors, generating a proximal-to-distal gradient of TGFβ sensitivity that can be altered with disruption of steady-state Notch signaling. In posttreatment biopsy samples, we observed significant immune depletion with expansion of fibrogenic niches, a process that can be reversed by inhibition of Notch and TGFβ signaling in RA patient-derived organoids. Collectively, our data implicate targeting of TGFβ signaling to prevent exuberant synovial tissue fibrosis as a potential therapeutic strategy for refractory RA.
Authors
- Michael R. Clay (ORCID: https://orcid.org/0000-0003-1659-8927)
- PATRICK M. CARRY
- Ksenia S. Anufrieva (ORCID: https://orcid.org/0000-0001-5558-8591)
- L. Donlin
- Annabelle Small (ORCID: https://orcid.org/0000-0001-6275-2847)
- Daniel K. Moon (ORCID: https://orcid.org/0000-0003-0899-1761)
- Susan M. Goodman (ORCID: https://orcid.org/0000-0003-1197-7864)
- Fraser J. Leversedge (ORCID: https://orcid.org/0000-0002-3810-3713)
- Michael J. Zuscik (ORCID: https://orcid.org/0000-0003-0461-8708)
- Michael R. Dayton (ORCID: https://orcid.org/0000-0003-4447-5465)
- Ranjeny Thomas
- Soon Wei Wong
- Andrew Clauw
- C. Pitzalis
- Melissa Griffith
- Vikram Khedgikar
- Adam P. Croft (ORCID: https://orcid.org/0000-0002-9487-0511)
- Jeffrey K. Lange (ORCID: https://orcid.org/0000-0002-6771-9007)
- Anna H Jonsson
- Sean A. Prell
- Adam Croft
- Christopher Altmann
- Kartik Bhamidipati
- Mihir D. Wechalekar (ORCID: https://orcid.org/0000-0001-6668-9638)
- PHILIP E. BLAZAR
- Terrin Geohring
- Ce Gao (ORCID: https://orcid.org/0000-0001-9804-261X)
- Miles Tran (ORCID: https://orcid.org/0009-0005-9330-9297)
- Shideh Kazerounian
- Mark Smith
- Sonia Presti
- Kevin Wei
- Accelerating Medicines Partnership RA/SLE Network
- Cherl L. Ackert-Bicknell
- Jennifer A. Seifert
- Rachel M. Frank
- Michael B. Brenner
- Ellen M. Gravallese
- Roopa Madhu
- Rachel Lau
- Alexa B. R. McIntyre
- V. Michael Holers
- Ilya Korsunsky
- Craig A. Hogan
- Myles J. Lewis
- Adam J. Seidl
Institutions
- Linköping University (SE)
- Broad Institute (US)
- Hospital for Special Surgery (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- The University of Queensland (AU)
- Queen Mary University of London (GB)
- Flinders University (AU)
- Cornell University (US)
- Barts Health NHS Trust (GB)
- Queen Elizabeth Hospital Birmingham (GB)
- Flinders Medical Centre (AU)
- Children's Hospital Colorado (US)
- William Harvey Research Institute (GB)
- Weill Cornell Medicine (US)
- University of Colorado Anschutz Medical Campus (US)
- Massachusetts Institute of Technology (US)
- University of Birmingham (GB)
- University of Colorado Denver (US)
Publication Details
- Journal
- Nature Immunology
- Published
- 2026-01-15
- DOI
- https://doi.org/10.1038/s41590-025-02386-2
- Citations
- 2
- Primary Topic
- Rheumatoid Arthritis Research and Therapies
- Type
- article
- Field-Weighted Citation Impact
- 93.60