PMID- 36708867
OWN - NLM
STAT- MEDLINE
DCOM- 20230529
LR  - 20230529
IS  - 1638-6183 (Electronic)
IS  - 0300-9084 (Linking)
VI  - 209
DP  - 2023 Jun
TI  - Melatonin activates mitochondrial unfolded protein response to preserve 
      osteogenic potential of senescent BMSCs via upregulating PDI-6.
PG  - 44-51
LID - S0300-9084(23)00015-9 [pii]
LID - 10.1016/j.biochi.2023.01.015 [doi]
AB  - Bone marrow stromal cells (BMSCs) possess the capability to differentiate into 
      osteogenic or adipogenic lineages. With aging, BMSCs suffer from mitochondrial 
      dysfunction and undergo senescence, favoring adipogenesis at the expense of 
      osteoblastogenesis. It leads to decreased bone formation and contributes to 
      senile osteoporosis (SOP). In the current study, RNA-seq analysis unveiled that 
      senescent BMSCs from mice exhibited a significant suppression in the expression 
      of the protein disulfide isomerase PDI-6, an important regulator of mitochondrial 
      unfolded protein response (UPR(mt)) as well as maintenance of mitochondrial 
      homeostasis. Overexpression of PDI-6 in senescent BMSCs partially rescued 
      mitochondrial function and enhanced osteogenic differentiation. In contrast, 
      osteoblastogenesis of BMSCs remarkably deteriorated under the condition of PDI-6 
      silencing. Furthermore, melatonin, an endocrine hormone, effectively enhanced 
      PDI-6 expression and repaired injured mitochondria, and the effect of melatonin 
      on PDI-6 expression was melatonin receptor dependent. We further identified that 
      PDI-6 was a downstream effector of Wnt/beta-catenin pathway, as the inhibitor of 
      Wnt3A/TCF signaling, Wnt-C59, inhibited PDI-6 expression. Potential 
      beta-catenin-TCF/LEF binding sites on the promoter of PDI-6 gene were also validated 
      by chromatin immunoprecipitation (ChIP) assay. Thus, our study suggests that 
      PDI-6 is a pharmacological target of melatonin for the intervention of 
      age-related osteoporosis via mitigating mitochondrial dysfunction in senescent 
      BMSCs.
CI  - Copyright (c) 2023. Published by Elsevier B.V.
FAU - Li, Feng
AU  - Li F
AD  - Department of Orthopaedics, Weifang People's Hospital, Weifang, Shandong, China.
FAU - Lun, Dengxing
AU  - Lun D
AD  - Department of Orthopaedics, Weifang People's Hospital, Weifang, Shandong, China.
FAU - Liu, Dayong
AU  - Liu D
AD  - Department of Orthopaedics, Weifang People's Hospital, Weifang, Shandong, China.
FAU - Jia, Zesen
AU  - Jia Z
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Tianjin Medical University, 22 Qixiangtai Rd, Heping, Tianjin, China.
FAU - Zhu, Zhenye
AU  - Zhu Z
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Tianjin Medical University, 22 Qixiangtai Rd, Heping, Tianjin, China.
FAU - Liu, Zhiqiang
AU  - Liu Z
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Tianjin Medical University, 22 Qixiangtai Rd, Heping, Tianjin, China.
FAU - Li, Xiaopeng
AU  - Li X
AD  - Department of Orthopaedics, Weifang People's Hospital, Weifang, Shandong, China. 
      Electronic address: rmyylixiaopeng@wfmc.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20230126
PL  - France
TA  - Biochimie
JT  - Biochimie
JID - 1264604
RN  - JL5DK93RCL (Melatonin)
RN  - 0 (beta Catenin)
SB  - IM
MH  - Mice
MH  - Animals
MH  - Osteogenesis
MH  - *Melatonin/pharmacology/metabolism
MH  - beta Catenin/metabolism
MH  - *Mesenchymal Stem Cells/metabolism
MH  - Cell Differentiation
MH  - *Osteoporosis/drug therapy/metabolism
MH  - Aging
MH  - Unfolded Protein Response
MH  - Bone Marrow Cells/metabolism
MH  - Wnt Signaling Pathway
MH  - Cells, Cultured
OTO - NOTNLM
OT  - Bone marrow stromal cells
OT  - Melatonin
OT  - Mitochondrial unfolded protein response
OT  - PDI-6
OT  - Senile osteoporosis
COIS- Declaration of competing interest The authors declare no competing financial 
      interests.
EDAT- 2023/01/29 06:00
MHDA- 2023/05/29 06:42
CRDT- 2023/01/28 19:25
PHST- 2022/10/03 00:00 [received]
PHST- 2023/01/04 00:00 [revised]
PHST- 2023/01/18 00:00 [accepted]
PHST- 2023/05/29 06:42 [medline]
PHST- 2023/01/29 06:00 [pubmed]
PHST- 2023/01/28 19:25 [entrez]
AID - S0300-9084(23)00015-9 [pii]
AID - 10.1016/j.biochi.2023.01.015 [doi]
PST - ppublish
SO  - Biochimie. 2023 Jun;209:44-51. doi: 10.1016/j.biochi.2023.01.015. Epub 2023 Jan 
      26.