engleski

Mid1 is a novel mediator of subchondral bone resorption in antigen-induced arthritis

Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune joint disease characterized by subchondral bone destruction not reversible by currently available therapeutics. We have shown that mice deficient for Fas gene (Fas-/-) are protected from local bone resorption in antigen-induced arthritis (AIA), a murine model of RA, and have a lower frequency of synovial myeloid cells, which downregulate Mid1 gene. The objective of the study was to evaluate the role of Mid1 in bone resorption in AIA. Materials and methods: After receiving ethical approval, arthritis was induced by immunization of mice with methylated bovine serum albumin (mBSA) with subsequent intra articular injection of mBSA. Synovial myeloid (CD11b + Gr- 1 +) cell transcriptome was analyzed by Affymetrix ST 2.0 arrays. Bioinformatics analysis was performed using Bioconductor. Differences in gene expression were confirmed by qRT-PCR. WT-AIA mice were treated in vivo with metformin, which inhibits proinflammatory effect of Mid1, at daily dose 1 g/kg, to assess effects on arthritis development. Results: Mid1 gene was up-regulated in myeloid cells (logFC = 2.01, p(BH-adjusted) = 0.0003, limma BH-adjustment) and bulk joint tissue (logFC = 8.74, p = 0.02, Welch-test) of WT mice in comparison to Fas-/- mice with non-resorptive arthritis. Despite its position on X chromosome Mid1 expression in joints was not sexually dimorphic and was up-regulated in WT- AIA in both male (logFC = 1.92, p = 0.006, T-test) and female mice (logFC = 8.74, p = 0.02, Welch-test). Furthermore, expression positively correlated with knee diameter (r = 0.68, p = 0.03, Spearman's rank correlation) and levels of pro-inflammatory cytokines in arthritis joints (IL-1: r = 0.78, p = 0.008 ; IL-6: r = 0.70, p = 0.025 ; TNF:r = 78, p = 0.008, Spearman's rank correlation). Metformin treatment of WT-AIA mice ameliorated the severity of arthritis assessed by knee diameter (3.69 ± 0.21 mm WT-AIA vs. 3.36 ± 0.12 mm WT-AIA ? metformin, p = 0.008, T-test). Conclusions: Mid1 is a novel mediator of subchondral bone destruction in arthritis and its inhibition might present a new therapeutic target for inflammation-mediated joint destruction.

Mid1, Bone resorption, Arthritis

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