Background/Purpose: Axial Spondyloarthritis (AxSpA) is characterized by both inflammation and new bone formation. Current therapeutic targets aim to control inflammation, however over 40% of patients do not respond to them. The novel deubiquitinase molecule TRABID has been shown to epigenetically control the expression of IL12/23 in the experimental autoimmune encephalomyelitis mouse model. Furthermore, our group has previously shown significantly increased expression of TRABID in inflamed human SpA tissues (bone marrow, synovium and gut). We have also shown that the inhibition of TRABID in monocyte and osteoblast cell culture models significantly supresses cytokine production and bone mineralization respectively. Furthermore, TRABID inhibition in-vivo in curdlan-treated SKG mice significantly suppresses the clinical and histopathological signs of arthritis. Therefore, this study aims to understand the genetic and proteomic mechanisms behind these phenotypes.

Methods: To understand if TRABID can contribute to new bone formation in the spine, facet joint tissues from 5 AxSpA and 5 disease controls were stained using immunohistochemistry to determine TRABID expression patterns. Furthermore, TRABID interactome during osteogenesis was identified by proximity-dependant biotin identification (BioID). Cells were transfected with miniTurbo-tagged TRABID constructs and incubated for 6 days in McCoy’s growth or osteogenic media. Biotinylated proteins were enriched using streptavidin beads and identified by mass spectrometry. Biological pathways associated with top significant interactors were identified using PathDip. To assess in-vivo transcriptomic changes induced by TRABID inhibition, 8-week-old SKG mice were injected with curdlan or PBS. For 8 weeks, mice received PBS or high-dose TRABID inhibitor NSC112200 (300mM/kg every 2 days). At 16 weeks, ankle/lymph nodes were collected for RNA extraction and transcriptomic profiling using the murine Nanostring Immunology panel. Pathway analysis for overrepresented gene sets was conducted using Gene Set Enrichment Analysis (GSEA).

Results: We found that TRABID was significantly overexpressed by periosteal cells, osteochondroprogenitor cells that have been shown to promote new bone formation, in the AxSpA facet joints compared to disease controls. Excitingly, we find that TRABID significantly and uniquely interacts with signal transduction, tight junction markers and Rho GTPases during osteogenesis. Moreover, these interactors were predominantly associated with the actin cytoskeleton and membrane bound vesicles. Finally, TRABID inhibition in-vivo significantly altered the expression of genes that belong to antigen processing and presentation pathways in SKG mice. Moreover, these altered genes were found to be associated with the endocytic vesicle membrane and MHC protein complex.

Conclusion: Taken together, our data suggests that TRABID may contribute to new bone formation and inflammation in AxSpA by regulating vesicle transport within the cell. Future work will focus on identifying the exact mechanism by which this process occurs to contribute to AxSpA disease pathology.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-deubiquitinase-trabid-is-a-regulator-of-osteogenesis-and-inflammation-in-spondyloarthritis/