The Rheumatoid Arthritis Risk Gene LBH Regulates Growth in Fibroblast‐like Synoviocytes

• Published in: Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2015-05, Vol.67 (5), p.1193-1202
• Main Authors: Ekwall, Anna‐Karin H., Whitaker, John W., Hammaker, Deepa, Bugbee, William D., Wang, Wei, Firestein, Gary S.
• Format: Article
• Language: English
• Subjects: Apoptosis - genetics; Arthritis, Rheumatoid - genetics; Becaplermin; Case-Control Studies; Cell cycle; Cell growth; Cell Movement - genetics; Cell Proliferation - genetics; Cells, Cultured; DNA methylation; Fibroblasts - drug effects; Fibroblasts - metabolism; Gene expression; Gene Expression Profiling; Gene Silencing; Humans; Osteoarthritis - genetics; Proto-Oncogene Proteins c-sis - pharmacology; Reumatologi och inflammation; Rheumatology and Autoimmunity; RNA, Messenger - metabolism; RNA, Small Interfering; Synovial Membrane - cytology; Synovial Membrane - metabolism; Trans-Activators - drug effects; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription Factors; Transforming Growth Factor beta1 - pharmacology
• ISSN: 2326-5191; 2326-5205; 2326-5205
• DOI: 10.1002/art.39060

Objective Fibroblast‐like synoviocytes (FLS) are key players in the synovial pathology of rheumatoid arthritis (RA). Currently, there is no treatment that specifically targets these aggressive cells. By combining 3 different “omics” data sets, i.e., 1) risk genes in RA, 2) differentially expressed genes, and 3) differential DNA methylation in RA versus osteoarthritis (OA) FLS, we identified LBH (limb bud and heart development) as a candidate gene in RA. The present study was undertaken to define the role of this gene in FLS. Methods Synovial tissue specimens from RA and OA patients were collected at the time of joint replacement surgery. LBH expression was silenced using small interfering RNA or overexpressed using an LBH expression vector in primary FLS. Gene expression profiles were determined by microarray and assessed using Ingenuity Pathway Analysis. Effects of modified LBH expression were investigated in functional assays. Results LBH was expressed in the synovial lining layer in patients with RA. Transforming growth factor β1 significantly increased LBH expression in primary FLS, and platelet‐derived growth factor BB decreased it. Pathway analysis of the transcriptome of LBH‐deficient FLS compared to control FLS identified “cellular growth and proliferation” as the most significantly enriched pathway. In growth assays, LBH deficiency increased FLS proliferation. Conversely, LBH overexpression significantly inhibited cell growth. Cell cycle analysis demonstrated a marked increase in cells entering the cell cycle in LBH‐deficient FLS compared to controls. LBH did not alter apoptosis. Conclusion LBH is a candidate gene for synovial pathology in RA. It is regulated by growth factors and modulates cell growth in primary FLS. Our data suggest a novel mechanism for synovial intimal hyperplasia and joint damage in RA.