ArticleScience signaling2018
Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition.
Article in Science signaling, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
21 citing papers in PubMed, 28 citations in OpenAlex.
- Systems biology framework for the rational design of operational conditions for in vitro/in vivo translation of tissue models.Science advances · 2026Article
- Epigenetic suppression of synovial inflammation and osteoclast differentiation in rheumatoid arthritis by I-BET762.Scientific reports · 2026Article
- Preclinical Pharmacokinetics, ADME, and Drug-Drug Interaction Evaluation of S024, a Novel p38/MK2 Inhibitor for Rheumatoid Arthritis.Drug design, development and therapy · 2026Article
- Losmapimod ameliorates doxorubicin-induced cardiotoxicity through attenuating senescence and inflammatory pathways.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2024Article
- Tropisetron attenuates neuroinflammation and chronic neuropathic pain via α7nAChR activation in the spinal cord in rats.The journal of spinal cord medicine · 2024Article
- Selective Inhibition of the MK2 Pathway: Data From a Phase IIa Randomized Clinical Trial in Rheumatoid Arthritis.ACR open rheumatology · 2023Article
- Specialized Pro-Resolving Mediators Do Not Inhibit the Synthesis of Inflammatory Mediators Induced by Tumor Necrosis Factor-α in Synovial Fibroblasts.Yonago acta medica · 2022Article
- MicroRNA-4423-3p inhibits proliferation of fibroblast-like synoviocytes by targeting matrix metalloproteinase 13 in rheumatoid arthritis.Bioengineered · 2021Article
- Untargeted metabolomics identifies succinate as a biomarker and therapeutic target in aortic aneurysm and dissection.European heart journal · 2021Article
- Targeting of Janus Kinases Limits Pro-Inflammatory but Also Immunosuppressive Circuits in the Crosstalk between Synovial Fibroblasts and Lymphocytes.Biomedicines · 2021Article
- Cell surface integrin α5ß1 clustering negatively regulates receptor tyrosine kinase signaling in colorectal cancer cells via glycogen synthase kinase 3.Integrative biology : quantitative biosciences from nano to macro · 2021Article
- A systematic analysis of signaling reactivation and drug resistance.Cell reports · 2021Article
- Diversity and versatility of p38 kinase signalling in health and disease.Nature reviews. Molecular cell biology · 2021Review
- Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the MK2 Inhibitor ATI-450 in Healthy Subjects: A Placebo-Controlled, Randomized Phase 1 Study.Clinical pharmacology : advances and applications · 2021Article
- Computational model predicts paracrine and intracellular drivers of fibroblast phenotype after myocardial infarction.Matrix biology : journal of the International Society for Matrix Biology · 2020Review
- Hi-Frontiers in medicine · 2020Review
- Substrate-based kinase activity inference identifies MK2 as driver of colitis.Integrative biology : quantitative biosciences from nano to macro · 2019Article
- Losartan suppresses the inflammatory response in collagen-induced arthritis by inhibiting the MAPK and NF-κB pathways in B and T cells.Inflammopharmacology · 2019Article
- Critical role of IL-1α in IL-1β-induced inflammatory responses: cooperation with NF-κBp65 in transcriptional regulation.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Article
- Development and application of human skeletal muscle microphysiological systems.Lab on a chip · 2018Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disorder that causes joint pain, swelling, and loss of function. Development of effective new drugs has proven challenging in part because of the complexities and interconnected nature of intracellular signaling networks that complicate the effects of pharmacological interventions. We characterized the kinase signaling pathways that are activated in RA and evaluated the multivariate effects of targeted inhibitors. Synovial fluids from RA patients activated the kinase signaling pathways JAK, JNK, p38, and MEK in synovial fibroblasts (SFs), a stromal cell type that promotes RA progression. Kinase inhibitors enhanced signaling of "off-target" pathways in a manner dependent on stimulatory context. Inhibitors of p38, which have been widely explored in clinical trials for RA, resulted in undesirable increases in nuclear factor κB (NF-κB), JNK, and MEK signaling in SFs in inflammatory, but not mitogenic, contexts. This was mediated by the transcription factor CREB, which functions in part within a negative feedback loop in MAPK signaling. CREB activation was induced predominately by p38 in response to inflammatory stimuli, but by MEK in response to mitogenic stimuli; hence, the effects of drugs targeting p38 or MEK were markedly different in SFs cultured under mitogenic or inflammatory conditions. Together, these findings illustrate how stimulatory context can alter dominance in pathway cross-talk even for a fixed network topology, thereby providing a rationale for why p38 inhibitors deliver limited benefits in RA and demonstrating the need for careful consideration of p38-targeted drugs in inflammation-related disorders.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.