Sungyong Youa,1, Seung-Ah Yoob,1, Susanna Choib, Ji-Young Kimb, Su-Jung Parkb, Jong Dae Jic, Tae-Hwan Kimd, Ki-Jo Kimb,e, Chul-Soo Chob,e, Daehee Hwanga,f,2, and Wan-Uk Kimb,e,2
aSchool of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang 790-784, Korea;
bPOSTECH-Catholic BioMedical Engineering Institute and
eDepartment of Internal Medicine, Catholic University of Korea, Seoul 137-701, Korea;
cDivision of Rheumatology, College of Medicine, Korea University, Seoul 137-701, Korea;
dHospital for Rheumatic Disease, Hanyang University, Seoul 133-792, Korea; and
fCenter for Systems Biology of Plant Senescence and Life History, Institute for Basic Science, Daegu Gyeongbuk Institute of Science and Technology, Daegu 711-873, Korea
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.
1S.Y. and S.-A.Y. contributed equally to this work.
2To whom correspondence may be addressed.
Author contributions: S.Y., S.-A.Y., C.-S.C., D.H., and W.-U.K. designed research; S.Y., S.-A.Y., S.C., J.-Y.K., S.-J.P., C.-S.C., D.H., and W.-U.K. performed research; W.-U.K. contributed new reagents/analytic tools; S.Y., S.-A.Y., S.C., J.-Y.K., S.-J.P., J.D.J., T.-H.K., K.-J.K., C.-S.C., D.H., and W.-U.K. analyzed data; and S.Y., S.-A.Y., K.-J.K., D.H., and W.-U.K. wrote the paper.