PMID- 32427355
OWN - NLM
STAT- MEDLINE
DCOM- 20210615
LR  - 20211204
IS  - 1523-4681 (Electronic)
IS  - 0884-0431 (Linking)
VI  - 35
IP  - 10
DP  - 2020 Oct
TI  - Intracellular Accumulation of Advanced Glycation End Products Induces Osteoblast 
      Apoptosis Via Endoplasmic Reticulum Stress.
PG  - 1992-2003
LID - 10.1002/jbmr.4053 [doi]
AB  - Osteoporosis is an aging-associated disease that is attributed to excessive 
      osteoblast apoptosis. It is known that the accumulation of advanced glycation end 
      products (AGEs) in bone extracellular matrix deteriorates osteoblast functions. 
      However, little is known about the interaction between intracellular AGE 
      accumulation and the induction of osteoblast apoptosis. In this study, we 
      investigated the effect of intracellular AGE accumulation on osteoblast apoptosis 
      in vitro and in vivo. In vitro, murine osteoblastic MC3T3-E1 cells were treated 
      with glycolaldehyde (GA), an AGE precursor. GA-induced intracellular AGE 
      accumulation progressed in time- and dose-dependent manners, followed by 
      apoptosis induction. Intracellular AGE formation also activated endoplasmic 
      reticulum (ER) stress-related proteins (such as glucose-regulated protein 78, 
      inositol-requiring protein-1alpha (IRE1alpha), and c-Jun N-terminal kinase) and induced 
      apoptosis. In agreement, treatment with the ER stress inhibitor 4-phenylbutyric 
      acid and knocking down IRE1alpha expression ameliorated osteoblast apoptosis. 
      Furthermore, the ratio between AGE- and terminal deoxynucleotidyl 
      transferase-mediated dUTP nick end labeling (TUNEL)-positive osteoblasts in human 
      vertebral bodies was significantly higher in an elderly group than in a younger 
      group. A positive linear correlation between the ratio of AGE-positive and 
      TUNEL-positive osteoblasts (r = 0.72) was also observed. Collectively, these 
      results indicate that AGEs accumulated in osteoblasts with age and that 
      intracellular AGE accumulation induces apoptosis via ER stress. These findings 
      offer new insight into the mechanisms of osteoblast apoptosis and age-related 
      osteoporosis. (c) 2020 American Society for Bone and Mineral Research.
CI  - (c) 2020 American Society for Bone and Mineral Research.
FAU - Suzuki, Ryusuke
AU  - Suzuki R
AUID- ORCID: 0000-0002-7759-0673
AD  - Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, 
      Japan.
AD  - Laboratory of Food and Regulation Biology, School of Agriculture, Tokai 
      University, Kumamoto, Japan.
FAU - Fujiwara, Yukio
AU  - Fujiwara Y
AD  - Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto 
      University, Kumamoto, Japan.
FAU - Saito, Mitsuru
AU  - Saito M
AD  - Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, 
      Japan.
FAU - Arakawa, Shoutaro
AU  - Arakawa S
AD  - Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, 
      Japan.
FAU - Shirakawa, Jun-Ichi
AU  - Shirakawa JI
AD  - Laboratory of Food and Regulation Biology, School of Agriculture, Tokai 
      University, Kumamoto, Japan.
FAU - Yamanaka, Mikihiro
AU  - Yamanaka M
AD  - Laboratory of Food and Regulation Biology, School of Agriculture, Tokai 
      University, Kumamoto, Japan.
FAU - Komohara, Yoshihiro
AU  - Komohara Y
AD  - Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto 
      University, Kumamoto, Japan.
FAU - Marumo, Keishi
AU  - Marumo K
AD  - Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, 
      Japan.
FAU - Nagai, Ryoji
AU  - Nagai R
AD  - Laboratory of Food and Regulation Biology, School of Agriculture, Tokai 
      University, Kumamoto, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200605
PL  - England
TA  - J Bone Miner Res
JT  - Journal of bone and mineral research : the official journal of the American 
      Society for Bone and Mineral Research
JID - 8610640
RN  - 0 (Glycation End Products, Advanced)
RN  - EC 2.7.11.1 (Ern1 protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 3.1.- (Endoribonucleases)
SB  - IM
MH  - 3T3 Cells
MH  - Animals
MH  - *Apoptosis
MH  - *Endoplasmic Reticulum Stress
MH  - Endoribonucleases
MH  - Glycation End Products, Advanced/*metabolism
MH  - Humans
MH  - Mice
MH  - Osteoblasts/*cytology
MH  - Protein Serine-Threonine Kinases
OTO - NOTNLM
OT  - ADVANCED GLYCATION END PRODUCTS
OT  - APOPTOSIS
OT  - ENDOPLASMIC RETICULUM STRESS
OT  - OSTEOBLAST
EDAT- 2020/05/20 06:00
MHDA- 2021/06/16 06:00
CRDT- 2020/05/20 06:00
PHST- 2019/11/30 00:00 [received]
PHST- 2020/05/01 00:00 [revised]
PHST- 2020/05/13 00:00 [accepted]
PHST- 2020/05/20 06:00 [pubmed]
PHST- 2021/06/16 06:00 [medline]
PHST- 2020/05/20 06:00 [entrez]
AID - 10.1002/jbmr.4053 [doi]
PST - ppublish
SO  - J Bone Miner Res. 2020 Oct;35(10):1992-2003. doi: 10.1002/jbmr.4053. Epub 2020 
      Jun 5.