Advanced glycation end products suppress osteoblastic differentiation of stromal cells by activating endoplasmic reticulum stress.
Advanced glycation end products (AGEs) are involved in bone quality deterioration in diabetes mellitus. We previously showed that AGE2 or AGE3 inhibited osteoblastic differentiation and mineralization of mouse stromal ST2 cells, and also induced apoptosis and decreased cell growth. Although quality management for synthesized proteins in endoplasmic reticulum (ER) is crucial for the maturation of osteoblasts, the effects of AGEs on ER stress in osteoblast lineage are unknown. We thus examined roles of ER stress in AGE2- or AGE3-induced suppression of osteoblastogenesis of ST2 cells. An ER stress inducer, thapsigargin (TG), induced osteoblastic differentiation of ST2 cells by increasing the levels of Osterix, type 1 collagen (Col1), alkaline phosphatase (ALP) and osteocalcin (OCN) mRNA. AGE2 or AGE3 suppressed the levels of ER stress sensors such as IRE1α, ATF6 and OASIS, while they increased the levels of PERK and its downstream molecules, ATF4. A reduction in PERK level by siRNA did not affect the AGEs-induced suppression of the levels of Osterix, Col1 and OCN mRNA. In conclusion, AGEs inhibited the osteoblastic differentiation of stromal cells by suppressing ER stress sensors and accumulating abnormal proteins in the cells. This process might accelerate AGEs-induced suppression of bone formation found in diabetes mellitus.
Department of Internal Medicine 1, Shimane University Faculty of Medicine, Izumo, Japan. ken1nai@med.shimane-u.ac.jp
Ken-ichiro
K
Tanaka
Toru
T
Yamaguchi
Hiroshi
H
Kaji
Ippei
I
Kanazawa
Toshitsugu
T
Sugimoto
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology*; D017154:Stromal Cells / Q000166:cytology* / Q000187:drug effects; D019284:Thapsigargin / Q000494:pharmacology
D017127:Glycation End Products, Advanced; D019284:Thapsigargin
ATF; Advanced glycation end products; Bone; Diabetes; Endoplasmic reticulum stress; IRE; OASIS; Osteoblastogenesis; PERK; Stromal cells; activating transcription factor; inositol-requiring transmembrane kinase and endonuclease; old astrocyte specifically induced substance; protein kinase RNA-like endoplasmic reticulum kinase