RRC ID 45039
Author Notsu M, Yamaguchi T, Okazaki K, Tanaka K, Ogawa N, Kanazawa I, Sugimoto T.
Title Advanced glycation end product 3 (AGE3) suppresses the mineralization of mouse stromal ST2 cells and human mesenchymal stem cells by increasing TGF-β expression and secretion.
Journal Endocrinology
Abstract In diabetic patients, advanced glycation end products (AGEs) cause bone fragility because of deterioration of bone quality. We previously showed that AGEs suppressed the mineralization of mouse stromal ST2 cells. TGF-β is abundant in bone, and enhancement of its signal causes bone quality deterioration. However, whether TGF-β signaling is involved in the AGE-induced suppression of mineralization during the osteoblast lineage remains unknown. We therefore examined the roles of TGF-β in the AGE-induced suppression of mineralization of ST2 cells and human mesenchymal stem cells. AGE3 significantly (P < .001) inhibited mineralization in both cell types, whereas transfection with small interfering RNA for the receptor for AGEs (RAGEs) significantly (P < .05) recovered this process in ST2 cells. AGE3 increased (P < .001) the expression of TGF-β mRNA and protein, which was partially antagonized by transfection with RAGE small interfering RNA. Treatment with a TGF-β type I receptor kinase inhibitor, SD208, recovered AGE3-induced decreases in osterix (P < .001) and osteocalcin (P < .05) and antagonized the AGE3-induced increase in Runx2 mRNA expression in ST2 cells (P < .001). Moreover, SD208 completely and dose dependently rescued AGE3-induced suppression of mineralization in both cell types. In contrast, SD208 intensified AGE3-induced suppression of cell proliferation as well as AGE3-induced apoptosis in proliferating ST2 cells. These findings indicate that, after cells become confluent, AGE3 partially inhibits the differentiation and mineralization of osteoblastic cells by binding to RAGE and increasing TGF-β expression and secretion. They also suggest that TGF-β adversely affects bone quality not only in primary osteoporosis but also in diabetes-related bone disorder.
Volume 155(7)
Pages 2402-10
Published 2014-7-1
DOI 10.1210/en.2013-1818
PMID 24758301
MeSH Animals Apoptosis / drug effects Calcification, Physiologic / drug effects* Cell Line Cell Proliferation / drug effects Core Binding Factor Alpha 1 Subunit / genetics Core Binding Factor Alpha 1 Subunit / metabolism Enzyme-Linked Immunosorbent Assay Gene Expression / drug effects Glycation End Products, Advanced / pharmacology* Humans Mesenchymal Stem Cells / drug effects* Mesenchymal Stem Cells / metabolism Mice Osteocalcin / genetics Osteocalcin / metabolism Protein Kinase Inhibitors / pharmacology Protein Serine-Threonine Kinases / antagonists & inhibitors Protein Serine-Threonine Kinases / metabolism RNA Interference Receptor for Advanced Glycation End Products Receptor, Transforming Growth Factor-beta Type I Receptors, Immunologic / genetics Receptors, Immunologic / metabolism Receptors, Transforming Growth Factor beta / antagonists & inhibitors Receptors, Transforming Growth Factor beta / metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction / drug effects Signal Transduction / genetics Sp7 Transcription Factor Stromal Cells / drug effects* Stromal Cells / metabolism Transcription Factors / genetics Transcription Factors / metabolism Transforming Growth Factor beta / genetics Transforming Growth Factor beta / metabolism*
IF 3.934
Times Cited 21
Human and Animal Cells ST2(RCB0224)