USP15-dependent modulation of TGF-β/Smad2/3 signaling: implications for chondrocyte matrix degradation and autophagy in osteoarthritis
Year: 2025
Type: article
Abstract: The dysregulation of extracellular matrix (ECM) metabolism and autophagy in chondrocytes is central to osteoarthritis (OA) pathogenesis, yet the molecular mechanisms remain poorly defined. Ubiquitin-specific protease 15 (USP15), a key modulator of TGF-β/Smad2/3 signaling through TβR-I stabilization, may play a critical role in maintaining chondrocyte homeostasis. We conducted in vitro and ex vivo experiments using OA patient-derived cartilage samples and chondrocyte models to test the hypotheses that (1) USP15 deficiency exacerbates OA progression by impairing TGF-β/Smad2/3 signaling, leading to ECM degradation and autophagy dysfunction; and (2) restoring USP15 expression activates this pathway to mitigate cartilage degeneration, an effect reversible by TGF-β/Smad inhibition. Lentiviral-mediated USP15 knockdown or overexpression, combined with pharmacological inhibition assays, revealed that reduced USP15 levels in OA lesions correlated with disease severity (Kellgren-Lawrence grading) and triggered ECM catabolism (downregulated Col-II, MMP-13), suppressed autophagy (reduced LC3-II, accumulated p62), and increased apoptosis. Conversely, USP15 overexpression stabilized TβR-I, enhanced TGF-β/Smad2/3 signaling activity, increased Smad2/3 protein expression and promoted Smad2/3 phosphorylation(p < 0.01), and restored ECM synthesis and autophagic flux. These protective effects were abolished by the TGF-β receptor kinase inhibitor SIS3 (p < 0.001), confirming pathway dependency. Our findings establish USP15 as a pivotal regulator of chondrocyte homeostasis via the TβR-I/Smad axis, offering novel therapeutic targets for OA intervention.
Source: Scientific Reports
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,690
OpenAlex ID: W4415735027