# Mechanical Load‐Induced Upregulation of Talin2 through Non‐Canonical Deubiquitination of OTUB1 Drives Facet Joint Osteoarthritis Pathogenesis

## TL;DR

This study identifies Talin2 as a key player in facet joint osteoarthritis, showing how mechanical stress and a protein called OTUB1 contribute to joint degeneration.

## Contribution

The paper reveals a novel mechanism involving Talin2 stabilization through non-canonical deubiquitination by OTUB1 under mechanical load, linking it to FJOA progression.

## Key findings

- Talin2 is upregulated in FJOA and promotes extracellular matrix degradation while inhibiting its synthesis.
- Mechanical loading enhances Talin2 stabilization via OTUB1-mediated non-canonical deubiquitination.
- Talin2 upregulates CCL2, an inflammatory chemoattractant, exacerbating joint degeneration.

## Abstract

Facet joint osteoarthritis (FJOA) is a prevalent degenerative condition in the aging population; however, the underlying pathophysiological mechanisms remain poorly understood and current therapeutic strategies remain limited to palliative pain management. In this study, novel potential therapeutic targets and prevention paradigms for FJOA are systematically explored. Proteomic screening and validation show that Talin2 is specifically upregulated in FJOA samples. Immunoprecipitation‐mass spectrometry, transcriptome RNA sequencing, and bioinformatics simulation analyses, combined with in vitro and in vivo experiments, are conducted to elucidate the molecular mechanism of the role of Talin2 in FJOA. Increased expression levels of Talin2 in FJOA promote the degradation of the extracellular matrix and inhibit its synthesis. Talin2 is found to be stabilized via non‐canonical deubiquitination and direct interaction with ovarian tumor domain‐containing ubiquitin aldehyde‐binding protein 1 (OTUB1). C–C motif ligand 2 (CCL2), an inflammatory chemoattractant, is identified to be a target gene of Talin2. Furthermore, mechanical loading potentiates the Talin2/OTUB1 interaction, resulting in the stabilization of Talin2 and enhances non‐canonical deubiquitination. Therefore, Talin2 regulates CCL2 expression and promotes FJOA. Given that Talin2 is stabilized and deubiquitinated by OTUB1, especially under mechanical load, the Talin2/OTUB1 interaction may be a promising therapeutic target for FJOA.

Facet joint osteoarthritis (FJOA), prevalent in the elderly, involves Talin2 upregulation promoting ECM degradation while suppressing synthesis. Mechanical load stabilizes Talin2 via OTUB1‐mediated non‐canonical deubiquitination, driving CCL2 expression that recruits immune cells, exacerbating inflammatory joint degeneration. The role of the Talin2/OTUB1/CCL2 axis in mechanical load‐inflammatory conversion, suggesting novel potential preventive and therapeutic strategies for FJOA is revealed.