Identification of key regulators for the migration and invasion of rheumatoid synoviocytes through a systems approach

Abstract

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.

Review: The Tumor‐Like Phenotype of Rheumatoid Synovium: Molecular Profiling and Prospects for Precision Medicine

“…Metabolite changes have been described in the serum, urine, and synovial fluid of RA patients, and include both changes in amino acid and lipid metabolism and a dysregulation in glycolysis with increased lactate production (83-85) that has been attributed to the tumor-like phenomenon of aerobic glycolysis, or the Warburg effect (86). Aerobic glycolysis characterizes (80). Next, the differentially methylated gene (DMG) signature was obtained (74).…”

“…Comparative view of different “omics” profiles and pathologic signatures of rheumatoid fibroblast‐like synoviocytes ( FLS ). Differentially expressed genes ( DEG s) were first screened using transcriptome data on FLS from patients with rheumatoid arthritis ( RA ) and patients with osteoarthritis ( OA ) . Next, the differentially methylated gene ( DMG ) signature was obtained .…”

TGFβ responsive tyrosine phosphatase promotes rheumatoid synovial fibroblast invasiveness

“…We next examined whether PTPRK ASO inhibits the in vivo invasiveness of RA FLS in a recently reported invasion assay 30. We induced skin inflammation in athymic nude mice by subcutaneously injecting complete Freund's adjuvant, and then intradermally implanted RA FLS pretreated with Ctl or PTPRK ASO.…”

Placental Growth Factor-1 and -2 Induce Hyperplasia and Invasiveness of Primary Rheumatoid Synoviocytes

“…The wound migration of RA-FLSs was measured as described previously (25). In brief, FLSs plated to confluence on a six-well plate were wounded with pipette tips and then treated with IL-1b or PlGF in DMEM supple-mented with 1% FBS.…”

“…The BD BioCoat Matrigel invasion chamber assay system (Becton Dickinson, Heidelberg, Germany) was used to evaluate FLS invasion, according to the manufacturer's instructions (25). Briefly, 24 h after transfection with siRNA, RA-FLSs were allowed to migrate in a Matrigel layer chamber for an additional 12 h in the presence of DMEM containing 10% FBS or 10 ng/ml IL-1b in DMEM supplemented with 1% FBS.…”