USP13 mediates PTEN to ameliorate osteoarthritis by restraining oxidative stress, apoptosis and inflammation via AKT-dependent manner
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...
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doaj-54b8ee012b0843f28f7b25ffe48903892021-05-21T04:19:36ZengElsevierBiomedicine & Pharmacotherapy0753-33222021-01-01133111089USP13 mediates PTEN to ameliorate osteoarthritis by restraining oxidative stress, apoptosis and inflammation via AKT-dependent mannerJianming Huang0Zhiyang Ye1Jun Wang2Qichuan Chen3Danlei Huang4Haoyuan Liu5Corresponding authors.; Department of Orthopedics, Chenggong Hospital of Xiamen University (the 73th Group Military Hospital of People’s Liberation Army), Xiamen 361003, ChinaDepartment of Orthopedics, Chenggong Hospital of Xiamen University (the 73th Group Military Hospital of People’s Liberation Army), Xiamen 361003, ChinaDepartment of Orthopedics, Chenggong Hospital of Xiamen University (the 73th Group Military Hospital of People’s Liberation Army), Xiamen 361003, ChinaDepartment of Orthopedics, Chenggong Hospital of Xiamen University (the 73th Group Military Hospital of People’s Liberation Army), Xiamen 361003, ChinaDepartment of Orthopedics, Chenggong Hospital of Xiamen University (the 73th Group Military Hospital of People’s Liberation Army), Xiamen 361003, ChinaCorresponding authors.; Department of Orthopedics, Chenggong Hospital of Xiamen University (the 73th Group Military Hospital of People’s Liberation Army), Xiamen 361003, ChinaOsteoarthritis 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.http://www.sciencedirect.com/science/article/pii/S0753332220312828OsteoarthritisUSP13PTENAKT |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jianming Huang Zhiyang Ye Jun Wang Qichuan Chen Danlei Huang Haoyuan Liu |
spellingShingle |
Jianming Huang Zhiyang Ye Jun Wang Qichuan Chen Danlei Huang Haoyuan Liu USP13 mediates PTEN to ameliorate osteoarthritis by restraining oxidative stress, apoptosis and inflammation via AKT-dependent manner Biomedicine & Pharmacotherapy Osteoarthritis USP13 PTEN AKT |
author_facet |
Jianming Huang Zhiyang Ye Jun Wang Qichuan Chen Danlei Huang Haoyuan Liu |
author_sort |
Jianming Huang |
title |
USP13 mediates PTEN to ameliorate osteoarthritis by restraining oxidative stress, apoptosis and inflammation via AKT-dependent manner |
title_short |
USP13 mediates PTEN to ameliorate osteoarthritis by restraining oxidative stress, apoptosis and inflammation via AKT-dependent manner |
title_full |
USP13 mediates PTEN to ameliorate osteoarthritis by restraining oxidative stress, apoptosis and inflammation via AKT-dependent manner |
title_fullStr |
USP13 mediates PTEN to ameliorate osteoarthritis by restraining oxidative stress, apoptosis and inflammation via AKT-dependent manner |
title_full_unstemmed |
USP13 mediates PTEN to ameliorate osteoarthritis by restraining oxidative stress, apoptosis and inflammation via AKT-dependent manner |
title_sort |
usp13 mediates pten to ameliorate osteoarthritis by restraining oxidative stress, apoptosis and inflammation via akt-dependent manner |
publisher |
Elsevier |
series |
Biomedicine & Pharmacotherapy |
issn |
0753-3322 |
publishDate |
2021-01-01 |
description |
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. |
topic |
Osteoarthritis USP13 PTEN AKT |
url |
http://www.sciencedirect.com/science/article/pii/S0753332220312828 |
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