Resource and Technical AdvanceIn-Press PreviewInflammation Open Access | 10.1172/jci.insight.179392
1Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, United States of America
2Department of Medicine, University of California, San Diego, La Jolla, United States of America
Find articles by Choi, E. in: JCI | PubMed | Google Scholar
1Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, United States of America
2Department of Medicine, University of California, San Diego, La Jolla, United States of America
Find articles by Machado, C. in: JCI | PubMed | Google Scholar
1Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, United States of America
2Department of Medicine, University of California, San Diego, La Jolla, United States of America
Find articles by Okano, T. in: JCI | PubMed | Google Scholar
1Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, United States of America
2Department of Medicine, University of California, San Diego, La Jolla, United States of America
Find articles by Boyle, D. in: JCI | PubMed | Google Scholar
1Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, United States of America
2Department of Medicine, University of California, San Diego, La Jolla, United States of America
Find articles by Wang, W. in: JCI | PubMed | Google Scholar
1Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, United States of America
2Department of Medicine, University of California, San Diego, La Jolla, United States of America
Find articles by Firestein, G. in: JCI | PubMed | Google Scholar
Published May 23, 2024 - More info
The mechanisms responsible for the distribution and severity of joint involvement in rheumatoid arthritis (RA) are not known. To explore whether site-specific FLS biology might be associated with location-specific synovitis and explain the predilection for hand (wrist/metacarpal phalangeal joints) involvement in RA, we generated transcriptomic and chromatin accessibility data from FLS to identify the transcription factors (TFs) and pathways. Networks were constructed by integration of chromatin accessibility and gene expression data. Analysis revealed joint-specific patterns of FLS phenotype, with proliferative, migratory, proinflammatory, and matrix-degrading characteristics observed in resting FLS derived from the hand joints compared with hip or knee. TNF-stimulation amplified these differences, with greater enrichment of proinflammatory and proliferative genes in hand FLS compared with hip and knee FLS. Hand FLS also had the greatest expression of markers associated with an ‘activated’ state relative to the ‘resting’ state, with the greatest cytokine and MMP expression in TNF-stimulated hand FLS. Predicted differences in proliferation and migration were biologically validated with hand FLS exhibiting greater migration and cell growth than hip or knee FLS. Distinctive joint-specific FLS biology associated with a more aggressive inflammatory response might contribute to the distribution and severity of joint involvement in RA.