DNA Demethylation Rescues the Impaired Osteogenic Differentiation Ability of Human Periodontal Ligament Stem Cells in High Glucose.
Diabetes mellitus, characterized by abnormally high blood glucose levels, gives rise to impaired bone remodeling. In response to high glucose (HG), the attenuated osteogenic differentiation capacity of human periodontal ligament stem cells (hPDLSCs) is associated with the loss of alveolar bone. Recently, DNA methylation was reported to affect osteogenic differentiation of stem cells in pathological states. However, the intrinsic mechanism linking DNA methylation to osteogenic differentiation ability in the presence of HG is still unclear. In this study, we found that diabetic rats with increased DNA methylation levels in periodontal ligaments exhibited reduced bone mass and density. In vitro application of 5-aza-2'-deoxycytidine (5-aza-dC), a DNA methyltransferase inhibitor, to decrease DNA methylation levels in hPDLSCs, rescued the osteogenic differentiation capacity of hPDLSCs under HG conditions. Moreover, we demonstrated that the canonical Wnt signaling pathway was activated during this process and, under HG circumstances, the 5-aza-dC-rescued osteogenic differentiation capacity was blocked by Dickkopf-1, an effective antagonist of the canonical Wnt signaling pathway. Taken together, these results demonstrate for the first time that suppression of DNA methylation is able to facilitate the osteogenic differentiation capacity of hPDLSCs exposed to HG, through activation of the canonical Wnt signaling pathway.
Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Southwest Medical University, Luzhou 646000, P.R. China.|National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, P.R. China.|State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, P.R. China.
Zhi
Z
Liu
National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, P.R. China.|State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, P.R. China.|Department of Orthodontics, West China School of Stomatology, Sichuan University, Chengdu 610041, P.R. China.
Tian
T
Chen
National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, P.R. China.|State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, P.R. China.
Wenhua
W
Sun
Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Southwest Medical University, Luzhou 646000, P.R. China.
Zongyi
Z
Yuan
National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, P.R. China.|State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, P.R. China.
Mei
M
Yu
National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, P.R. China.|State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, P.R. China.
Guoqing
G
Chen
National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, P.R. China.|State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, P.R. China.
Weihua
W
Guo
Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Southwest Medical University, Luzhou 646000, P.R. China.|Orofacial Reconstruction and Regeneration Laboratory, Hospital of Stomatology, Southwest Medical University, Luzhou 646000, P.R. China.
Jingang
J
Xiao
National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, P.R. China.|State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, P.R. China.|Department of Oral and Maxillofacial Surgery, West China School of Stomatology, Sichuan University, Chengdu 610041, P.R. China.
Weidong
W
Tian
D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015519:Bone Density; D002454:Cell Differentiation / Q000187:drug effects; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000378:metabolism; D019175:DNA Methylation; D000077209:Decitabine; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D005947:Glucose / Q000008:administration & dosage*; D006801:Humans; D010012:Osteogenesis; D010513:Periodontal Ligament / Q000166:cytology*; D051381:Rats; D013234:Stem Cells / Q000166:cytology*; D051153:Wnt Proteins / Q000378:metabolism
D051153:Wnt Proteins; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; C000619380:DNMT1 protein, human; D005947:Glucose; D001374:Azacitidine