The Deubiquitinase Molecule TRABID: A Novel Therapeutic Target for Axial Spondyloarthritis
Bibliographic record
Abstract
Objectives Inflammation and new bone formation are important disease mediators in axial spondyloarthritis (axSpA). Recent studies in mice show that the deubiquitinase TRABID epigenetically controls the expression of IL12/23 through JMJD2D (Jumonji Domain-Containing Protein 2D). Furthermore, TRABID also upregulates EZH2 (Enhancer of zeste homolog 2), a molecule that has been implicated in pro-osteogenic pathways in breast cancer. This study aims to study the functional and clinical relevance of TRABID in axSpA pathogenesis. Methods To evaluate differential expressions of TRABID in human and mouse axSpA, human spine, gut, bone marrow and synovium and mouse ankle and tail were analyzed by immunohistochemistry and qPCR. Then, to assess the effect of TRABID inhibition on cytokine production, THP-1 cells (monocyte cell line) and splenocytes from SKG mice were incubated with lipopolysaccharide (LPS) and varying concentrations of NSC112200, an inhibitor of TRABID. ELISA detected cytokine production after 24 hours and western blot evaluated expression of EZH2 and JMJD2D. To evaluate TRABID’s role in osteogenesis, TRABID was knocked down in Saos-2 cells (osteoblast cell line) using siRNAs to evaluate the effect of TRABID expression on osteogenesis. RNA was extracted to evaluate osteogenic gene expression by qPCR and RNA sequencing. Calcium mineralization was evaluated by Alizarin Red staining. Finally, to assess the in vivo clinical relevance of TRABID inhibition, curdlan injected SKG mice were treated for 8 weeks with NSC112200. Results Our results showed that TRABID is significantly upregulated in all human tissue tested and SKG mouse ankle and tail compared to healthy controls. THP-1 cells and SKG mouse splenocytes treated with NSC112200 and LPS together showed a dose dependent inhibition of TNFa, IL1b and IL23 production when compared with cells treated with only LPS. Furthermore, TRABID inhibition showed a significant downregulation in both JMJD2D and EZH2 protein levels. TRABID knockdown in Saos-2 cells showed significant suppression of pro-osteogenic genes SP7, Runx2 and alkaline phosphatase and failed to mineralize. RNA sequencing confirmed pathways related to TGFb signaling, bone remodeling and endochondral ossification were suppressed. Osteogenic media upregulated TRABID expression over time, compared with cells treated with unconditioned growth media. Finally, NSC112200 dose dependently suppressed clinical and histopathological signs of arthritis and inflammation in curdlan injected SKG mice. Nanostring analysis showed downregulation of genes related to immune cell migration to the inflamed joint with TRABID inhibition. Conclusion TRABID inhibition is a promising new target to control disease progression in axSpA. Future work will address downstream cellular mechanisms of TRABID. Best Abstract on Spondyloarthritis Research Award
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".