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Identification of key regulators for the migration and invasion of rheumatoid synoviocytes through a systems approach
- Identification of key regulators for the migration and invasion of rheumatoid synoviocytes through a systems approach
- You, S[You, Sungyong]; Yoo, SA[Yoo, Seung-Ah]; Choi, S[Choi, Susanna]; Kim, JY[Kim, Ji-Young]; Park, SJ[Park, Su-Jung]; Ji, JD[Ji, Jong Dae]; Kim, TH[Kim, Tae-Hwan]; Kim, KJ[Kim, Ki-Jo]; Cho, CS[Cho, Chul-Soo]; Hwang, D[Hwang, Daehee]; Kim, WU[Kim, Wan-Uk]
- DGIST Authors
- Hwang, D[Hwang, Daehee]
- Issue Date
- Proceedings of the National Academy of Sciences of the United States of America, 111(1), 550-555
- Article Type
- Arthritis, Rheumatoid; Cell Adhesion Molecules; Cell Invasion; Cell Migration; Cell Movement; Chronic Inflammation; Cluster Analysis; Fibroblasts; Gene Expression Profiling; Gene Expression Regulation; Humans; Inflammation; Interleukin-1 Beta; Intracellular Signaling Peptides and Proteins; LIM Domain Proteins; Macrophages; Models, Biological; Nuclear Proteins; Osteoarthritis; Priority Journal; Protein; Protein Expression; Protein Twist1; Rheumatoid Arthritis; Synovial Membrane; Synoviocyte; Synovitis; Systems Biology; Systems Theory; Transcription Factor RUNX2; Transcriptome; Twist Transcription Factor; Unclassified Drug
- Rheumatoid synoviocytes, which consist of fibroblast-like synoviocytes (FLSs) and synovial macrophages (SMs), are crucial for the progression of rheumatoid arthritis (RA). Particularly, FLSs of RA patients (RA-FLSs) exhibit invasive characteristics reminiscent of cancer cells, destroying cartilage and bone. RA-FLSs and SMs originate differently from mesenchymal and myeloid cells, respectively, but share many pathologic functions. However, the molecular signatures and biological networks representing the distinct and shared features of the two cell types are unknown. We performed global transcriptome profiling of FLSs and SMs obtained from RA and osteoarthritis patients. By comparing the transcriptomes, we identified distinct molecular signatures and cellular processes defining invasiveness of RA-FLSs and proinflammatory properties of RA-SMs, respectively. Interestingly, under the interleukin-1β (IL-1β)-stimulated condition, the RA-FLSs newly acquired proinflammatory signature dominant in RA-SMs without losing invasive properties. We next reconstructed a network model that delineates the shared, RA-FLS-dominant (invasive), and RA-SM-dominant (inflammatory) processes. From the network model, we selected 13 genes, including periostin, osteoblast-specific factor (POSTN) and twist basic helix-loop-helix transcription factor 1 (TWIST1), as key regulator candidates responsible for FLS invasiveness. Of note, POSTN and TWIST1 expressions were elevated in independent RA-FLSs and further instigated by IL-1β. Functional assays demonstrated the requirement of POSTN and TWIST1 for migration and invasion of RA-FLSs stimulated with IL-1β. Together, our systems approach to rheumatoid synovitis provides a basis for identifying key regulators responsible for pathological features of RA-FLSs and -SMs, demonstrating how a certain type of cells acquires functional redundancy under chronic inflammatory conditions.
- National Academy of Sciences
- Related Researcher
Hwang, Dae Hee
Systems Biology and Medicine Lab
Multilayered spatiotemporal networks; Regulatory motifs or pathways; Metabolite-protein networks; Network stochasticity; Proteomics and informatics
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