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<p>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 <i>COMP</i> 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.</p>

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Spatial patterning of fibroblast TGFβ signaling underlies treatment resistance in rheumatoid arthritis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月15日

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  • Kartik Bhamidipati,
  • Alexa B. R. McIntyre,
  • Shideh Kazerounian,
  • Gao Ce,
  • Soon W. Wong,
  • Miles Tran,
  • Sean A. Prell,
  • Rachel Lau,
  • Vikram Khedgikar,
  • Christopher Altmann,
  • Annabelle Small,
  • Roopa Madhu,
  • Sonia R. Presti,
  • Ksenia S. Anufrieva,
  • Philip E. Blazar,
  • Jeffrey K. Lange,
  • Jennifer A. Seifert,
  • Laura T. Donlin,
  • Laura T. Donlin,
  • Melanie H. Smith,
  • Ranjeny Thomas,
  • Michael J. Zuscik,
  • Michael R. Clay,
  • Andrew D. Clauw,
  • Melissa Griffith,
  • Terrin Geohring,
  • Patrick M. Carry,
  • V. Michael Holers,
  • Cherl L. Ackert-Bicknell,
  • Daniel Moon,
  • Craig A. Hogan,
  • Rachel M. Frank,
  • Michael R. Dayton,
  • Fraser J. Leversedge,
  • Adam J. Seidl,
  • Larry W. Moreland,
  • Adam P. Croft,
  • Melanie H. Smith,
  • Laura T. Donlin,
  • Myles J. Lewis,
  • Anna H. Jonsson,
  • Costantino Pitzalis,
  • Ranjeny Thomas,
  • Ellen M. Gravallese,
  • Michael B. Brenner,
  • Ilya Korsunsky,
  • Mihir D. Wechalekar,
  • Kevin Wei

摘要

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.