PMID- 36915137
OWN - NLM
STAT- MEDLINE
DCOM- 20230320
LR  - 20230320
IS  - 1749-799X (Electronic)
IS  - 1749-799X (Linking)
VI  - 18
IP  - 1
DP  - 2023 Mar 13
TI  - Metformin regulates chondrocyte senescence and proliferation through 
      microRNA-34a/SIRT1 pathway in osteoarthritis.
PG  - 198
LID - 10.1186/s13018-023-03571-5 [doi]
LID - 198
AB  - BACKGROUND: Osteoarthritis (OA) is the most common degenerative disease in joints 
      among elderly patients. Senescence is deeply involved in the pathogenesis of 
      osteoarthritis. Metformin is widely used as the first-line drug for Type 2 
      diabetes mellitus (T2DM), and has great potential for the treatment of other 
      aging-related disorders, including OA. However, the role of metformin in OA is 
      not fully elucidated. Therefore, our aim here was to investigate the effects of 
      metformin on human chondrocytes. METHODS: After metformin treatment, expression 
      level of microRNA-34a and SIRT1 in chondrocyte were detected with quantitative 
      real-time PCR and immunofluorescence staining. Then, microRNA-34a mimic and small 
      interfering RNA (siRNA) against SIRT1 (siRNA-SIRT1) were transfected into 
      chondrocyte. Senescence-associated beta-galactosidase (SA-beta-gal) staining was 
      performed to assess chondrocyte senescence. Chondrocyte viability was illustrated 
      with MTT and colony formation assays. Western blot was conducted to detect the 
      expression of P16, IL-6, matrix metalloproteinase-13 (MMP-13), Collagen type II 
      (COL2A1) and Aggrecan (ACAN). RESULTS: We found that metformin treatment (1 mM) 
      inhibited microRNA-34a while promoted SIRT1 expression in OA chondrocytes. Both 
      miR-34a mimics and siRNA against SIRT1 inhibited SIRT1 expression in 
      chondrocytes. SA-beta-gal staining assay confirmed that metformin reduced 
      SA-beta-gal-positive rate of chondrocytes, while transfection with miR-34a mimics or 
      siRNA-SIRT1 reversed it. MTT assay and colony formation assay showed that 
      metformin accelerated chondrocyte proliferation, while miR-34a mimics or 
      siRNA-SIRT1 weakened this effect. Furthermore, results from western blot 
      demonstrated that metformin suppressed expression of senescence-associated 
      protein P16, proinflammatory cytokine IL-6 and catabolic gene MMP-13 while 
      elevated expression of anabolic proteins such as Collagen type II and Aggrecan, 
      which could be attenuated by transfection with miR-34a mimics. CONCLUSION: 
      Overall, our data suggest that metformin regulates chondrocyte senescence and 
      proliferation through microRNA-34a/SIRT1 pathway, indicating it could be a novel 
      strategy for OA treatment.
CI  - (c) 2023. The Author(s).
FAU - Yan, Shiju
AU  - Yan S
AD  - Department of Orthopedics, Hainan Hospital of Chinese PLA General Hospital, 80 
      Jianglin Road, Sanya, Hainan, People's Republic of China.
FAU - Dong, Wenjing
AU  - Dong W
AD  - Department of Gerontology, Hainan Hospital of Chinese PLA General Hospital, 
      Sanya, People's Republic of China.
FAU - Li, Zhirui
AU  - Li Z
AD  - Department of Orthopedics, Hainan Hospital of Chinese PLA General Hospital, 80 
      Jianglin Road, Sanya, Hainan, People's Republic of China.
FAU - Wei, Junqiang
AU  - Wei J
AD  - Department of Orthopedics, Hainan Hospital of Chinese PLA General Hospital, 80 
      Jianglin Road, Sanya, Hainan, People's Republic of China.
FAU - Han, Tao
AU  - Han T
AD  - Department of Orthopedics, Hainan Hospital of Chinese PLA General Hospital, 80 
      Jianglin Road, Sanya, Hainan, People's Republic of China.
FAU - Wang, Junliang
AU  - Wang J
AD  - Department of Orthopedics, Hainan Hospital of Chinese PLA General Hospital, 80 
      Jianglin Road, Sanya, Hainan, People's Republic of China.
FAU - Lin, Feng
AU  - Lin F
AD  - Department of Orthopedics, Hainan Hospital of Chinese PLA General Hospital, 80 
      Jianglin Road, Sanya, Hainan, People's Republic of China. lyf1011@aliyun.com.
LA  - eng
PT  - Journal Article
DEP - 20230313
PL  - England
TA  - J Orthop Surg Res
JT  - Journal of orthopaedic surgery and research
JID - 101265112
RN  - 0 (Aggrecans)
RN  - 0 (Collagen Type II)
RN  - 0 (Interleukin-6)
RN  - EC 3.4.24.- (Matrix Metalloproteinase 13)
RN  - 9100L32L2N (Metformin)
RN  - 0 (MicroRNAs)
RN  - 0 (RNA, Small Interfering)
RN  - EC 3.5.1.- (SIRT1 protein, human)
RN  - EC 3.5.1.- (Sirtuin 1)
SB  - IM
MH  - Humans
MH  - Aggrecans/genetics/metabolism
MH  - Cell Proliferation/genetics
MH  - Chondrocytes/metabolism
MH  - Collagen Type II/genetics/metabolism
MH  - Diabetes Mellitus, Type 2
MH  - Interleukin-6/metabolism
MH  - Matrix Metalloproteinase 13/genetics/metabolism
MH  - *Metformin/pharmacology
MH  - *MicroRNAs/genetics/metabolism
MH  - *Osteoarthritis/drug therapy/genetics/metabolism
MH  - RNA, Small Interfering
MH  - Sirtuin 1/genetics/metabolism
PMC - PMC10012483
OTO - NOTNLM
OT  - Metformin
OT  - MicroRNA-34a
OT  - Osteoarthritis
OT  - Proliferation
OT  - SIRT1
OT  - Senescence
COIS- All authors have declared no conflict of interest.
EDAT- 2023/03/15 06:00
MHDA- 2023/03/16 06:00
PMCR- 2023/03/13
CRDT- 2023/03/14 01:28
PHST- 2022/08/21 00:00 [received]
PHST- 2023/01/31 00:00 [accepted]
PHST- 2023/03/14 01:28 [entrez]
PHST- 2023/03/15 06:00 [pubmed]
PHST- 2023/03/16 06:00 [medline]
PHST- 2023/03/13 00:00 [pmc-release]
AID - 10.1186/s13018-023-03571-5 [pii]
AID - 3571 [pii]
AID - 10.1186/s13018-023-03571-5 [doi]
PST - epublish
SO  - J Orthop Surg Res. 2023 Mar 13;18(1):198. doi: 10.1186/s13018-023-03571-5.