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

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.