PMID- 30584213
OWN - NLM
STAT- MEDLINE
DCOM- 20190522
LR  - 20191210
IS  - 1881-7823 (Electronic)
IS  - 1881-7815 (Linking)
VI  - 12
IP  - 6
DP  - 2019 Jan 22
TI  - Protective effects of metformin against osteoarthritis through upregulation of 
      SIRT3-mediated PINK1/Parkin-dependent mitophagy in primary chondrocytes.
PG  - 605-612
LID - 10.5582/bst.2018.01263 [doi]
AB  - Mitochondrial damage is involved in the pathogenesis of osteoarthritis. 
      Metformin, one of the most common prescriptions for patients with type 2 
      diabetes, can reportedly activate Sirtuin 3 (SIRT3) expression which protects 
      mitochondria from oxidative stress. In this study, we investigated the inhibitory 
      property of metformin on mitochondrial damage by focusing on the interleukin-1 
      beta (IL-1beta)-stimulated osteoarthritis model by using primary murine 
      chondrocytes. Our results demonstrated that SIRT3 was downregulated in 
      chondrocytes under IL-1beta stimulation, where its expression was positively 
      correlated with mitochondrial damage and reactive oxygen species (ROS) 
      production. Metformin treatment upregulated SIRT3 expression and mitigated loss 
      of cell viability and decreased the generation of mitochondria-induced ROS in 
      chondrocytes stimulated with IL-1beta. Metformin also attenuated IL-1beta-induced 
      expressions of catabolic genes such as matrix metalloproteinase-3 (MMP3) and 
      MMP13 and enhanced the anabolic indicator Collagen Ⅱ. These effects were mediated 
      by phosphatase and tensin homolog (PTEN)-induced putative kinase protein 1 
      (PINK1)/Parkin-dependent mitophagy and the autophagic elimination of damaged 
      mitochondria. Further, the SIRT3 inhibitor 3-TYP effectively inhibited the 
      initiation of mitophagy, as decreased expression of PINK1 and Parkin, decreased 
      the LC3II/LC3I, enhanced the expression of MMP3 and MMP13, and decreased the 
      expression of Collagen Ⅱ. Overall, our findings provide evidence that metformin 
      suppresses IL-1beta-induced oxidative and osteoarthritis-like inflammatory changes 
      by enhancing the SIRT3/PINK1/Parkin signaling pathway, thereby indicating 
      metformin's potential in prevention and treatment of osteoarthritic joint 
      disease.
FAU - Wang, Chenzhong
AU  - Wang C
AD  - Department of Orthopedic surgery, Zhongshan Hospital, Fudan University.
FAU - Yang, Yi
AU  - Yang Y
AD  - Department of Orthopedic surgery, Zhongshan Hospital, Fudan University.
FAU - Zhang, Yueqi
AU  - Zhang Y
AD  - Department of Orthopedic surgery, Zhongshan Hospital, Fudan University.
FAU - Liu, Jinyu
AU  - Liu J
AD  - Department of Orthopedic surgery, Zhongshan Hospital, Fudan University.
FAU - Yao, Zhenjun
AU  - Yao Z
AD  - Department of Orthopedic surgery, Zhongshan Hospital, Fudan University.
FAU - Zhang, Chi
AU  - Zhang C
AD  - Department of Orthopedic surgery, Zhongshan Hospital, Fudan University.
LA  - eng
PT  - Journal Article
DEP - 20181222
PL  - Japan
TA  - Biosci Trends
JT  - Bioscience trends
JID - 101502754
RN  - 0 (Interleukin-1beta)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Sirt3 protein, mouse)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.3.2.27 (parkin protein)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.11.1 (PTEN-induced putative kinase)
RN  - EC 3.5.1.- (Sirtuin 3)
SB  - IM
MH  - Animals
MH  - Cartilage, Articular/cytology
MH  - Cell Survival/drug effects/immunology
MH  - Cells, Cultured
MH  - Chondrocytes
MH  - Disease Models, Animal
MH  - Humans
MH  - Interleukin-1beta/immunology
MH  - Male
MH  - Metformin/*pharmacology/therapeutic use
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mitophagy/*drug effects/immunology
MH  - Osteoarthritis/*drug therapy/immunology
MH  - Primary Cell Culture
MH  - Protein Kinases/metabolism
MH  - Reactive Oxygen Species/immunology/metabolism
MH  - Sirtuin 3/antagonists & inhibitors/immunology/*metabolism
MH  - Treatment Outcome
MH  - Ubiquitin-Protein Ligases/metabolism
MH  - Up-Regulation/drug effects/immunology
OTO - NOTNLM
OT  - Osteoarthritis
OT  - SIRT3
OT  - mitophagy
EDAT- 2018/12/26 06:00
MHDA- 2019/05/23 06:00
CRDT- 2018/12/26 06:00
PHST- 2018/12/26 06:00 [pubmed]
PHST- 2019/05/23 06:00 [medline]
PHST- 2018/12/26 06:00 [entrez]
AID - 10.5582/bst.2018.01263 [doi]
PST - ppublish
SO  - Biosci Trends. 2019 Jan 22;12(6):605-612. doi: 10.5582/bst.2018.01263. Epub 2018 
      Dec 22.