Advanced glycation end products impair bone marrow mesenchymal stem cells osteogenesis in periodontitis with diabetes via FTO-mediated N6-methyladenosine modification of sclerostin

Jie Zhou; Yanlin Zhu; Dongqing Ai; Mengjiao Zhou; Han Li; Guangyue Li; Leilei Zheng; Jinlin Song

doi:10.1186/s12967-023-04630-5

Advanced glycation end products impair bone marrow mesenchymal stem cells osteogenesis in periodontitis with diabetes via FTO-mediated N⁶-methyladenosine modification of sclerostin

J Transl Med. 2023 Nov 4;21(1):781. doi: 10.1186/s12967-023-04630-5.

Authors

Jie Zhou^{1

2

3}, Yanlin Zhu^{1

2

3}, Dongqing Ai^{1

2

3}, Mengjiao Zhou^{1

2

3}, Han Li^{1

2

3}, Guangyue Li^{1

2

3}, Leilei Zheng^{1

2

3}, Jinlin Song^{4

5

6}

Affiliations

¹ College of Stomatology, Chongqing Medical University, Chongqing, People's Republic of China.
² Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China.
³ Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China.
⁴ College of Stomatology, Chongqing Medical University, Chongqing, People's Republic of China. songjinlin@hospital.cqmu.edu.cn.
⁵ Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China. songjinlin@hospital.cqmu.edu.cn.
⁶ Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China. songjinlin@hospital.cqmu.edu.cn.

Abstract

Background: Diabetes mellitus (DM) and periodontitis are two prevalent diseases with mutual influence. Accumulation of advanced glycation end products (AGEs) in hyperglycemia may impair cell function and worsen periodontal conditions. N⁶-methyladenosine (m⁶A) is an important post-transcriptional modification in RNAs that regulates cell fate determinant and progression of diseases. However, whether m⁶A methylation participates in the process of periodontitis with diabetes is unclear. Thus, we aimed to investigate the effects of AGEs on bone marrow mesenchymal stem cells (BMSCs), elucidate the m⁶A modification mechanism in diabetes-associated periodontitis.

Methods: Periodontitis with diabetes were established by high-fat diet/streptozotocin injection and silk ligation. M⁶A modifications in alveolar bone were demonstrated by RNA immunoprecipitation sequence. BMSCs treated with AGEs, fat mass and obesity associated (FTO) protein knockdown and sclerostin (SOST) interference were evaluated by quantitative polymerase chain reaction, western blot, immunofluorescence, alkaline phosphatase and Alizarin red S staining.

Results: Diabetes damaged alveolar bone regeneration was validated in vivo. In vitro experiments showed AGEs inhibited BMSCs osteogenesis and influenced the FTO expression and m⁶A level in total RNA. FTO knockdown increased the m⁶A levels and reversed the AGE-induced inhibition of BMSCs differentiation. Mechanically, FTO regulated m⁶A modification on SOST transcripts, and AGEs affected the binding of FTO to SOST transcripts. FTO knockdown accelerated the degradation of SOST mRNA in presence of AGEs. Interference with SOST expression in AGE-treated BMSCs partially rescued the osteogenesis by activating Wnt Signaling.

Conclusions: AGEs impaired BMSCs osteogenesis by regulating SOST in an m⁶A-dependent manner, presenting a promising method for bone regeneration treatment of periodontitis with diabetes.

Keywords: Advanced glycation end products; Bone marrow mesenchymal stem cells; Diabetes mellitus; N 6-methyladenosine; Osteogenesis; Periodontitis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing* / genetics
Alpha-Ketoglutarate-Dependent Dioxygenase FTO* / genetics
Bone Marrow Cells / metabolism
Cell Differentiation
Cells, Cultured
Diabetes Mellitus*
Glycation End Products, Advanced / pharmacology
Humans
Mesenchymal Stem Cells*
Osteogenesis
Periodontitis* / genetics
RNA / metabolism

Substances

Alpha-Ketoglutarate-Dependent Dioxygenase FTO
FTO protein, human
Glycation End Products, Advanced
N-methyladenosine
RNA
SOST protein, human
Adaptor Proteins, Signal Transducing