Metformin limits osteoarthritis development and progression through activation of ampk signalling

Li，Jun1; Zhang，Bin2; Liu，Wei Xiao2; Lu，Ke3; Pan，Haobo3; Wang，Tingyu4; Oh，Chun Do1; Yi，Dan1; Huang，Jian1; Zhao，Lan1; Ning，Guangzhi2; Xing，Cong2; Xiao，Guozhi5; Liu-Bryan，Ru6; Feng，Shiqing2; Chen，Di1,3

2020

10.1136/annrheumdis-2019-216713

ANNALS OF THE RHEUMATIC DISEASES   影响因子和分区

0003-4967

1468-2060

Objectives: In this study, we aim to determine the effect of metformin on osteoarthritis (OA) development and progression. Methods: Destabilisation of the medial meniscus (DMM) surgery was performed in 10-week-old wild type and AMP-activated protein kinase (AMPK)α1 knockout (KO) mice. Metformin (4 mg/day in drinking water) was given, commencing either 2 weeks before or 2 weeks after DMM surgery. Mice were sacrificed 6 and 12 weeks after DMM surgery. OA phenotype was analysed by micro-computerised tomography (μCT), histology and pain-related behaviour tests. AMPKα1 (catalytic alpha subunit of AMPK) expression was examined by immunohistochemistry and immunofluorescence analyses. The OA phenotype was also determined by μCT and MRI in non-human primates. Results: Metformin upregulated phosphorylated and total AMPK expression in articular cartilage tissue. Mild and more severe cartilage degeneration was observed at 6 and 12 weeks after DMM surgery, evidenced by markedly increased Osteoarthritis Research Society International scores, as well as reduced cartilage areas. The administration of metformin, commencing either before or after DMM surgery, caused significant reduction in cartilage degradation. Prominent synovial hyperplasia and osteophyte formation were observed at both 6 and 12 weeks after DMM surgery; these were significantly inhibited by treatment with metformin either before or after DMM surgery. The protective effects of metformin on OA development were not observed in AMPKα1 KO mice, suggesting that the chondroprotective effect of metformin is mediated by AMPK signalling. In addition, we demonstrated that treatment with metformin could also protect from OA progression in a partial medial meniscectomy animal model in non-human primates. Conclusions: The present study suggests that metformin, administered shortly after joint injury, can limit OA development and progression in injury-induced OA animal models.

arthritis chondrocytes osteoarthritis treatment

SCI

英语

其他

NIA NIH HHS[R03 AG061460] ; BLRD VA[I01 BX002234]

Rheumatology

Rheumatology

WOS:000531391400024

BMJ PUBLISHING GROUP

CLINICAL MEDICINE

2-s2.0-85081692680

Scopus

1.Department of Orthopedic Surgery,Rush University Medical Center,Chicago,United States
2.Department of Orthopedics,Tianjin Medical University General Hospital,Tianjin,China
3.Research Center for Human Tissues and Organs Degeneration,Shenzhen Institutes of Advanced Technology,Chinese Academy of Sciences,Shenzhen,China
4.Department of Pharmacy,Shanghai Ninth People's Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai,China
5.School of Medicine,Southern University of Science and Technology,Shenzhen,China
6.Division of Rheumatology,Allergy and Immunology,San Diego Va Healthcare System,San Diego,United States

Li，Jun,Zhang，Bin,Liu，Wei Xiao,et al. Metformin limits osteoarthritis development and progression through activation of ampk signalling[J]. ANNALS OF THE RHEUMATIC DISEASES,2020,79(5):635-645.

Li，Jun.,Zhang，Bin.,Liu，Wei Xiao.,Lu，Ke.,Pan，Haobo.,...&Chen，Di.(2020).Metformin limits osteoarthritis development and progression through activation of ampk signalling.ANNALS OF THE RHEUMATIC DISEASES,79(5),635-645.

Li，Jun,et al."Metformin limits osteoarthritis development and progression through activation of ampk signalling".ANNALS OF THE RHEUMATIC DISEASES 79.5(2020):635-645.