Deubiquitinating Enzymes in Osteoarthritis: From Mechanisms to Therapeutic
Zhikun Yuan1, Guanhao Chen2, Yanhui Li3
1Department of Orthopedics, Shijie Hospital of Dongguan City, Dongguan, China.
Abstract:
Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage erosion, synovial inflammation and pain. Accumulating evidence demonstrates that deubiquitinating enzymes (DUBs) are critical regulators of OA pathogenesis through their ability to rescue key proteins from proteasomal degradation. Among them, USP7 stabilizes NOX4 to amplify ROS-NLRP3-dependent pyroptosis and cartilage catabolism; USP15 deubiquitinates ERK2 and SMAD2 to enhance TGF-β signaling and chondrocyte anabolism; USP13 sustains PTEN and IL-1R8/Sigirr to restrain PI3K/AKT/NF-κB-mediated inflammation and oxidative stress; USP3 and USP49 block TRAF6 ubiquitination and Wnt/β-catenin signaling to attenuate chondrocyte senescence and apoptosis; USP5 and USP14 promote NF-κB activation by stabilizing TRAF6 or deubiquitinating IκBα, driving chondrocyte dedifferentiation and matrix metalloproteinase expression. Pre-clinically, small-molecule USP7 inhibitors (P22077), USP14 inhibitors (IU1) and genetic silencing of USP15 or USP49 have all been shown to reduce cartilage loss and inflammatory pain in mouse OA models. Collectively, these findings establish DUBs as druggable nodes in OA and underscore the need for selective inhibitors that can safely modulate ubiquitin-dependent protein turnover in human joints.However, DUB research remains nascent, requiring further validation of their clinical efficacy and safety. This review elucidates DUB-mediated mechanisms in OA and discusses challenges in developing selective DUB inhibitors for future therapies.
Insights
Deubiquitinating enzymes (DUBs) play key roles in osteoarthritis (OA) by regulating protein stability. Targeting specific DUBs shows promise for developing new OA treatments, but further research is needed.
Area of Science:
- Biochemistry
- Molecular Biology
- Rheumatology
Background:
- Osteoarthritis (OA) is a degenerative joint disease involving cartilage erosion, inflammation, and pain.
- Deubiquitinating enzymes (DUBs) are crucial in OA pathogenesis by controlling protein degradation.
- Specific DUBs influence key pathways like inflammation, oxidative stress, and cell death in OA.
Purpose of the Study:
- To elucidate the mechanisms by which DUBs regulate OA pathogenesis.
- To review the potential of DUBs as therapeutic targets for OA.
- To discuss the challenges in developing selective DUB inhibitors for OA treatment.
Main Methods:
- Review of accumulating evidence on DUB functions in OA.
- Analysis of DUBs' roles in stabilizing or degrading key proteins involved in OA.
- Examination of pre-clinical data from DUB inhibitor studies in mouse OA models.
Main Results:
- DUBs like USP7, USP15, USP13, USP3, USP49, USP5, and USP14 differentially regulate OA pathways.
- Inhibiting or silencing specific DUBs (e.g., USP7, USP14, USP15, USP49) reduced cartilage loss and pain in mouse models.
- DUBs are identified as druggable targets for modulating protein turnover in OA.
Conclusions:
- DUBs are critical regulators of OA pathogenesis and represent promising therapeutic targets.
- Selective DUB inhibitors hold potential for treating OA by modulating ubiquitin-dependent protein turnover.
- Further validation of clinical efficacy and safety of DUB inhibitors is essential for future OA therapies.
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