MiR-378 overexpression attenuates high glucose-suppressed osteogenic differentiation through targeting CASP3 and activating PI3K/Akt signaling pathway.
Hyperglycemia is one of the possible causes for osteoporosis and bone fracture in diabetes mellitus. Here we modeled diabetes-induced osteoporosis in vitro using preosteoblastic cell line MC3T3-E1 and a diabetic mice model for in vivo studies. We found that in addition to reducing osteoblast viability and differentiation (mineralization), culture in elevated glucose down regulated microRNA-378 (miR-378) expression but ectopic miR-378 expression reversed the effects of high glucose. We identified caspase-3 (CASP3) as a target of miR-378 and showed that miR-378 repressed CASP3 mRNA and protein expression under high glucose condition. We further showed that both miR-378 expression and CASP3 silencing independently restored alkaline phosphatase (ALP) activity and the expression of osteoblastic differentiation markers Runt-related transcription factor 2 (Runx2), osteorix (Osx), collagen I (Col I), osteocalcin (OCN), and osteonectin (ON). We also found that under high glucose conditions miR-378 activated the PI3K/Akt signaling pathway and down regulated pro-apoptotic CytC, Apaf-1 and Bax proteins via the PI3K/Akt pathway. Collectively, these results suggest that miR-378 overexpression attenuates high glucose-suppressed osteogenic differentiation through targeting CASP3 and activating the PI3K/Akt pathway.
Department of Endocrinology and Metabolism, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine 100 Haining Road, Shanghai 200080, China.
Li
L
You
Department of Endocrinology and Metabolism, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine 100 Haining Road, Shanghai 200080, China.
Wensha
W
Gu
Department of Endocrinology and Metabolism, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine 100 Haining Road, Shanghai 200080, China.
Lin
L
Chen
Department of Endocrinology and Metabolism, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine 100 Haining Road, Shanghai 200080, China.
Ling
L
Pan
Department of Endocrinology and Metabolism, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine 100 Haining Road, Shanghai 200080, China.
Jinyu
J
Chen
Department of Endocrinology and Metabolism, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine 100 Haining Road, Shanghai 200080, China.
Yongde
Y
Peng
D016475:3T3 Cells; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002113:Calcification, Physiologic; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002470:Cell Survival; D024042:Collagen Type I / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D005947:Glucose / Q000378:metabolism*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000201:enzymology* / Q000473:pathology; D015675:Osteocalcin / Q000378:metabolism; D010012:Osteogenesis; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D000076182:Sp7 Transcription Factor; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
D024042:Collagen Type I; D050659:Core Binding Factor Alpha 1 Subunit; C546119:MIRN378 microRNA, mouse; D035683:MicroRNAs; C493716:Runx2 protein, mouse; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D015675:Osteocalcin; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D000469:Alkaline Phosphatase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D005947:Glucose
CASP3; MiR-378; PI3K/Akt signaling; high glucose; osteogenic differentiation