PMID- 37304218
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230613
IS  - 2214-031X (Print)
IS  - 2214-0328 (Electronic)
IS  - 2214-031X (Linking)
VI  - 40
DP  - 2023 May
TI  - Metformin attenuates diabetes-induced osteopenia in rats is associated with 
      down-regulation of the RAGE-JAK2-STAT1 signal axis.
PG  - 37-48
LID - 10.1016/j.jot.2023.05.002 [doi]
AB  - BACKGROUND: Osteopenia and fragile fractures are diabetes-associated 
      complications. Many hypoglycemic drugs have effects on bone metabolism. 
      Metformin, as is a prescribed medication for type 2 diabetes mellitus (T2DM), had 
      been reported to have osteoprotective effects beyond its hypoglycemic effect, 
      however the potential mechanism behind these effects remains unclear. In this 
      study, we aimed to investigate the comprehensive effects of metformin on bone 
      metabolism in T2DM rat model and elucidate the potential mechanism. METHODS: 
      Goto-Kakizaki spontaneous T2DM rats with significant hyperglycemia were treated 
      with/without metformin for 20 weeks. Glucose tolerance was tested and all rats 
      were weighed every two weeks. The osteoprotective effects of metformin in 
      diabetic rats were determined by quantifying serum bone biomarkers, mu-CT imaging, 
      histological staining, bone histomorphometry, and biomechanical properties 
      analyses. Potential targets of metformin in the treatment of T2DM and 
      osteoporosis were predicted using network pharmacology. The effects of metformin 
      on mesenchymal stem cells (C3H10) cultured in high glucose medium were evaluated 
      by CCK-8 assay, alkaline phosphatase (ALP) staining, qPCR and western blotting. 
      RESULTS: This study demonstrated that metformin significantly attenuated 
      osteopenia, decreased serum glucose and glycated serum protein (GSP) levels, 
      improved bone microarchitecture, and biomechanical properties in GK rats with 
      T2DM. Metformin significantly increased biomarkers of bone formation, and 
      significantly decreased muscle ubiquitin C (Ubc) expression. Network pharmacology 
      analysis found that signal transducer and activator of transcription1 (STAT1) 
      would be a potential target of metformin for regulating bone metabolism. 
      Metformin increased C3H10 ​cell viability in vitro, alleviated ALP inhibition 
      caused by hyperglycemia, increased the osteogenic gene expression of runt-related 
      transcription factor 2 (RUNX2), collagen type I alpha 1 (Col1a1), osteocalcin 
      (OCN), and ALP, while suppressing RAGE and STAT1 expression. Metformin also 
      increased the protein expression of Osterix and decreased that of RAGE, p-JAK2, 
      and p-STAT1. CONCLUSIONS: Our results demonstrate that metformin attenuated 
      osteopenia and improved bone microarchitecture in GK rats with T2DM and 
      significantly promoted stem cell osteogenic differentiation under high glucose 
      condition. The effects of metformin on bone metabolism are closely associated 
      with the suppression of RAGE-JAK2-STAT1 signaling axis. THE TRANSLATIONAL 
      POTENTIAL OF THIS ARTICLE: Our research provides experiment evidence and 
      potential mechanistic rationale for the use of metformin as an effective 
      candidate for diabetes-induced osteopenia treatment.
CI  - (c) 2023 The Authors.
FAU - Lin, Rui
AU  - Lin R
AD  - Zhanjiang Key Laboratory of Orthopaedic Technology and Trauma Treatment, 
      Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang, 524037, PR 
      China.
AD  - Guangdong Provincial Key Laboratory for Research and Development of Natural Drug, 
      School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, PR China.
AD  - Key Laboratory of Traditional Chinese Medicine for the Prevention and Treatment 
      of Infectious Diseases, Guangdong Provincial Administration of Traditional 
      Chinese Medicine(Central People's Hospital of Zhanjiang), Zhanjiang, 524037, PR 
      China.
FAU - Xu, Bilian
AU  - Xu B
AD  - Guangdong Provincial Key Laboratory for Research and Development of Natural Drug, 
      School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, PR China.
FAU - Ye, Zhiqiang
AU  - Ye Z
AD  - Guangdong Provincial Key Laboratory for Research and Development of Natural Drug, 
      School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, PR China.
FAU - Gao, Yin
AU  - Gao Y
AD  - Guangdong Provincial Key Laboratory for Research and Development of Natural Drug, 
      School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, PR China.
AD  - Marine Medical Research Institute of Zhanjiang, Zhanjiang, 524023, PR China.
FAU - Fang, Haiping
AU  - Fang H
AD  - Guangdong Provincial Key Laboratory for Research and Development of Natural Drug, 
      School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, PR China.
FAU - Song, Jintong
AU  - Song J
AD  - Zhanjiang Key Laboratory of Orthopaedic Technology and Trauma Treatment, 
      Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang, 524037, PR 
      China.
AD  - Guangdong Provincial Key Laboratory for Research and Development of Natural Drug, 
      School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, PR China.
AD  - Key Laboratory of Traditional Chinese Medicine for the Prevention and Treatment 
      of Infectious Diseases, Guangdong Provincial Administration of Traditional 
      Chinese Medicine(Central People's Hospital of Zhanjiang), Zhanjiang, 524037, PR 
      China.
FAU - Liang, Dahong
AU  - Liang D
AD  - Guangdong Provincial Key Laboratory for Research and Development of Natural Drug, 
      School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, PR China.
FAU - Liu, Lingna
AU  - Liu L
AD  - Guangdong Provincial Key Laboratory for Research and Development of Natural Drug, 
      School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, PR China.
AD  - Marine Medical Research Institute of Zhanjiang, Zhanjiang, 524023, PR China.
FAU - Hu, Zilong
AU  - Hu Z
AD  - Guangdong Provincial Key Laboratory for Research and Development of Natural Drug, 
      School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, PR China.
FAU - Zhang, Min
AU  - Zhang M
AD  - Guangdong Provincial Key Laboratory for Research and Development of Natural Drug, 
      School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, PR China.
FAU - Wei, Jinsong
AU  - Wei J
AD  - Department of Orthopedics, Affiliated Hospital of Guangdong Medical University, 
      Zhanjiang, 524000, PR China.
FAU - Deng, Feifu
AU  - Deng F
AD  - Department of Orthopedics, Affiliated Hospital of Guangdong Medical University, 
      Zhanjiang, 524000, PR China.
FAU - Zhong, Xiangxin
AU  - Zhong X
AD  - Department of Orthopedics, Affiliated Hospital of Guangdong Medical University, 
      Zhanjiang, 524000, PR China.
FAU - Cui, Liao
AU  - Cui L
AD  - Guangdong Provincial Key Laboratory for Research and Development of Natural Drug, 
      School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, PR China.
FAU - Liu, Yanzhi
AU  - Liu Y
AD  - Zhanjiang Key Laboratory of Orthopaedic Technology and Trauma Treatment, 
      Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang, 524037, PR 
      China.
AD  - Guangdong Provincial Key Laboratory for Research and Development of Natural Drug, 
      School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, PR China.
AD  - Marine Medical Research Institute of Zhanjiang, Zhanjiang, 524023, PR China.
AD  - Key Laboratory of Traditional Chinese Medicine for the Prevention and Treatment 
      of Infectious Diseases, Guangdong Provincial Administration of Traditional 
      Chinese Medicine(Central People's Hospital of Zhanjiang), Zhanjiang, 524037, PR 
      China.
LA  - eng
PT  - Journal Article
DEP - 20230603
PL  - Singapore
TA  - J Orthop Translat
JT  - Journal of orthopaedic translation
JID - 101625127
PMC - PMC10250823
OTO - NOTNLM
OT  - Bone
OT  - Diabetes
OT  - Fragility
OT  - Metformin
OT  - Osteopenia
OT  - Osteoporosis
COIS- The authors declare that they have no known competing financial interests or 
      personal relationships that could have appeared to influence the work reported in 
      this paper.
EDAT- 2023/06/12 06:42
MHDA- 2023/06/12 06:43
PMCR- 2023/06/03
CRDT- 2023/06/12 04:05
PHST- 2023/01/06 00:00 [received]
PHST- 2023/04/17 00:00 [revised]
PHST- 2023/05/08 00:00 [accepted]
PHST- 2023/06/12 06:43 [medline]
PHST- 2023/06/12 06:42 [pubmed]
PHST- 2023/06/12 04:05 [entrez]
PHST- 2023/06/03 00:00 [pmc-release]
AID - S2214-031X(23)00029-3 [pii]
AID - 10.1016/j.jot.2023.05.002 [doi]
PST - epublish
SO  - J Orthop Translat. 2023 Jun 3;40:37-48. doi: 10.1016/j.jot.2023.05.002. 
      eCollection 2023 May.