USP13 mediates PTEN to ameliorate osteoarthritis by restraining oxidative stress, apoptosis and inflammation via AKT-dependent manner
Autor: | Danlei Huang, Jianming Huang, Haoyuan Liu, Jun Wang, Qichuan Chen, Zhiyang Ye |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
Male
0301 basic medicine PTEN Osteoclasts Apoptosis medicine.disease_cause 0302 clinical medicine Osteogenesis Tensin Cells Cultured biology Chemistry General Medicine Middle Aged Synoviocytes Mice Inbred DBA 030220 oncology & carcinogenesis Tumor necrosis factor alpha Bone Remodeling Ubiquitin-Specific Proteases medicine.symptom Signal transduction Signal Transduction Inflammation RM1-950 03 medical and health sciences Endopeptidases Osteoarthritis medicine Animals Humans Collagen Type II Protein kinase B Aged Pharmacology Hyperplasia AKT PTEN Phosphohydrolase USP13 Arthritis Experimental Mice Inbred C57BL Oxidative Stress 030104 developmental biology Cancer research biology.protein Joints Therapeutics. Pharmacology Proto-Oncogene Proteins c-akt Oxidative stress |
Zdroj: | Biomedicine & Pharmacotherapy, Vol 133, Iss, Pp 111089-(2021) |
ISSN: | 0753-3322 |
Popis: | Osteoarthritis is a chronic, systemic and inflammatory disease. However, the pathogenesis and understanding of RA are still limited. Ubiquitin-specific protease 13 (USP13) belongs to the deubiquitinating enzyme (DUB) superfamily, and has been implicated in various cellular events. Nevertheless, its potential on RA progression has little to be investigated. In the present study, we found that USP13 expression was markedly up-regulated in synovial tissue samples from patients with RA, and was down-regulated in human fibroblast-like synoviocytes (H-FLSs) stimulated by interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α) or lipopolysaccharide (LPS). We then showed that over-expressing USP13 markedly suppressed inflammatory response, oxidative stress and apoptosis in H-FLSs upon IL-1β or TNF-α challenge, whereas USP13 knockdown exhibited detrimental effects. In addition, USP13-induced protective effects were associated with the improvement of nuclear factor erythroid 2-related factor 2 (Nrf-2) and the repression of Casapse-3. Furthermore, phosphatase and tensin homolog (PTEN) expression was greatly improved by USP13 in H-FLSs upon IL-1β or TNF-α treatment, whereas phosphorylated AKT expression was diminished. In response to IL-1β or TNF-α exposure, nuclear transcription factor κB (NF-κB) signaling pathway was activated, whereas being significantly restrained in H-FLSs over-expressing USP13. Mechanistically, USP13 directly interacted with PTEN. Of note, we found that USP13-regulated cellular processes including inflammation, oxidative stress and apoptotic cell death were partly dependent on AKT activation. Furthermore, USP13 over-expression effectively inhibited osteoclastogenesis and osteoclast-associated gene expression. The in vivo experiments finally confirmed that USP13 dramatically repressed synovial hyperplasia, inflammatory cell infiltration, cartilage damage and bone loss in collagen-induced arthritis (CIA) mice via the same molecular mechanisms detected in vitro. Taken together, these findings suggested that targeting USP13 may provide feasible therapies for RA. |
Databáze: | OpenAIRE |
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