Fibroblast-like Synoviocytes as Key Regulators of Homeostasis and Inflammation in the Joint Microenvironment of...

Background: The body maintains homeostasis by inflammation, and arthritis is related to autoimmunity or inflammation. Angiogenesis contributes to synovitis through angiogenic factors and proteolytic enzymes, while different inflammatory arthritis conditions, such as osteoarthritis and rheumatoid arthritis, share similar cytokine networks and immune cell populations. Notably, progressive joint damage can occur despite effective systemic immunosuppression, suggesting that local stromal-immune interactions within the joint microenvironment may sustain inflammation and tissue destruction. Methods: We conducted an exploratory single-cell RNA-sequencing analysis using publicly available datasets from the NCBI GEO database, including synovial tissue and synovial fluid samples. Cell-cell communication and transcriptional regulatory networks were inferred using CellChat and SCENIC. Results: Computational analyses suggested that, in RA, macrophage-associated signaling shifts from TNF-related pathways toward SPP1-associated patterns, coinciding with transcriptional features of MMP3⁺ fibroblast-like synoviocytes (FLS). FLS-FLS interactions were associated with FGF-related signaling across disease contexts. ANGPTL-related signaling patterns differed among arthritis subtypes, with ANGPTL4 more prominent in OA and PsA and ANGPTL2 more frequently in RA-related transcriptional programs. Conclusions: These findings provide an exploratory framework for stromal-immune interactions and ANGPTL-associated signaling across inflammatory arthritis. The therapies for PsA may focus on systemic immune modulation and preservation of joint structural integrity. For OA and RA, the highlight may target ANGPTL4 and ANGPTL2 in the early and late stages of disease progression. Given the reliance on computational inference, the results warrant further experimental validation.