Related Experiment Video
Updated: Mar 12, 2026
Generation of Induced-pluripotent Stem Cells Using Fibroblast-like Synoviocytes Isolated from Joints of Rheumatoid Arthritis Patients
Published on: October 16, 2016
Profiling drugs for rheumatoid arthritis that inhibit synovial fibroblast activation
Douglas S Jones1,2, Anne P Jenney1, Jennifer L Swantek3
1HMS LINCS Center, Laboratory of Systems Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
Abstract:
Activation of synovial fibroblasts (SFs) contributes to rheumatoid arthritis (RA) by damaging synovial membranes and generating inflammatory cytokines that recruit immune cells to the joint. In this paper we profile cytokine secretion by primary human SFs from healthy tissues and from donors with RA and show that SF activation by TNF, IL-1α, and polyinosinic-polycytidylic acid (Poly(I:C)) cause secretion of multiple cytokines found at high levels in RA synovial fluids. We used interaction multiple linear regression to quantify therapeutic and countertherapeutic drug effects across activators and donors and found that the ability of drugs to block SF activation was strongly dependent on the identity of the activating cytokine. (5z)-7-oxozeaenol (5ZO), a preclinical drug that targets transforming growth factor-β-activated kinase 1 (TAK1), was more effective at blocking SF activation across all contexts than the approved drug tofacitinib, which supports the development of molecules similar to 5ZO for use as RA therapeutics.
Insights
Synovial fibroblast activation drives rheumatoid arthritis (RA). Targeting transforming growth factor-β-activated kinase 1 (TAK1) with (5z)-7-oxozeaenol (5ZO) shows promise for blocking RA-driving inflammation more effectively than tofacitinib.
Area of Science:
- Immunology
- Rheumatology
- Cell Biology
Background:
- Synovial fibroblasts (SFs) are key players in rheumatoid arthritis (RA) pathogenesis.
- Activated SFs damage joints and release cytokines, attracting immune cells.
- Understanding SF activation mechanisms is crucial for developing RA therapies.
Purpose of the Study:
- To profile cytokine secretion from human SFs in healthy individuals and RA patients.
- To investigate the impact of different activators (TNF, IL-1α, Poly(I:C)) on SF cytokine profiles.
- To evaluate the efficacy of drugs targeting SF activation in RA.
Main Methods:
- Primary human SFs from healthy and RA donors were cultured.
- SFs were activated using tumor necrosis factor (TNF), IL-1α, and polyinosinic-polycytidylic acid (Poly(I:C)).
- Cytokine secretion was measured, and drug effects were analyzed using interaction multiple linear regression.
Main Results:
- SF activation by TNF, IL-1α, and Poly(I:C) induced secretion of multiple cytokines found in RA synovial fluid.
- Drug efficacy in blocking SF activation was highly dependent on the specific activating cytokine.
- (5z)-7-oxozeaenol (5ZO), a TAK1 inhibitor, demonstrated superior inhibition of SF activation compared to tofacitinib across various contexts.
Conclusions:
- SF activation is a significant contributor to RA.
- Targeting TAK1 with molecules like 5ZO represents a promising therapeutic strategy for RA.
- Drug efficacy is context-dependent, highlighting the need for tailored therapeutic approaches in RA treatment.
Related Concept Videos
01:24Drugs for Treatment of Crohn's Disease in IBD Using Biologic Agents: Anti-TNF
01:29Drugs for Treatment of Crohn's Disease in IBD Using Immunomodulatory Agents
01:20The JAK-STAT Signaling Pathway
01:21Drugs for Treatment of Crohn's Disease in IBD Using Glucocorticoids
01:19Antiasthma Drugs: Leukotriene Modifiers
Leukotriene modifiers work through two distinct mechanisms:
01:17Drugs Used in Lower Respiratory Disorders: Overview
Bronchodilators, the first step of respiration enhancement, come in various forms, each with its own mechanism...