JKAMP inhibits the osteogenic capacity of adipose-derived stem cells in diabetic osteoporosis by modulating the Wnt signaling pathway through intragenic DNA methylation

Stem Cell Research & Therapy

Jingang Xiao¹  Qing He²  Lang Wang²  Shuanglin Peng³  Gang Tao⁴  Yanjing Li⁵  Dexuan Xiao⁵  Sirong Shi⁵  Xiaoxiao Cai⁵ 

[1] Department of Oral and Maxillofacial Surgery, The Affiliated Stomatology Hospital of Southwest Medical University, 646000, Luzhou, China;National Key Clinical Specialty, The Affiliated Hospital of Southwest Medical University, 646000, Luzhou, China;Orofacial Reconstruction and Regeneration Laboratory, The Affiliated Stomatology Hospital of Southwest Medical University, 646000, Luzhou, China;Department of Oral Implantology, The Affiliated Stomatology Hospital of Southwest Medical University, 646000, Luzhou, China;Department of Oral and Maxillofacial Surgery, The Affiliated Stomatology Hospital of Southwest Medical University, 646000, Luzhou, China;State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, 610041, Chengdu, China;Department of Oral and Maxillofacial Surgery, The Affiliated Stomatology Hospital of Southwest Medical University, 646000, Luzhou, China;State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, 610041, Chengdu, China;National Key Clinical Specialty, The Affiliated Hospital of Southwest Medical University, 646000, Luzhou, China;Orofacial Reconstruction and Regeneration Laboratory, The Affiliated Stomatology Hospital of Southwest Medical University, 646000, Luzhou, China;State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, 610041, Chengdu, China;

关键词: DNA methylation;    JKAMP;    Wnt signaling pathway;    Adipose-derived stem cells;    Osteogenic differentiation;    Diabetic osteoporosis;   

DOI  :  10.1186/s13287-021-02163-6

来源: Springer

【 摘 要 】

BackgroundDiabetic osteoporosis (DOP) is a systemic metabolic bone disease caused by diabetes mellitus (DM). Adipose-derived stem cells (ASCs) play an important role in bone regeneration. Our previous study confirmed that ASCs from DOP mice (DOP-ASCs) have a lower osteogenesis potential compared with control ASCs (CON-ASCs). However, the cause of this poor osteogenesis has not been elucidated. Therefore, this study investigated the underlying mechanism of the decline in the osteogenic potential of DOP-ASCs from the perspective of epigenetics and explored methods to enhance their osteogenic capacity.MethodsThe expression level of JNK1-associated membrane protein (JKAMP) and degree of DNA methylation in CON-ASCs and DOP-ASCs were measured by mRNA expression profiling and MeDIP sequencing, respectively. JKAMP small interfering RNA (siRNA) and a Jkamp overexpression plasmid were used to assess the role of JKAMP in osteogenic differentiation of CON-ASCs and DOP-ASCs. Immunofluorescence, qPCR, and western blotting were used to measure changes in expression of Wnt signaling pathway-related genes and osteogenesis-related molecules after osteogenesis induction. Alizarin red and ALP staining was used to confirm the osteogenic potential of stem cells. Bisulfite-specific PCR (BSP) was used to detect JKAMP methylation degree.ResultsExpression of JKAMP and osteogenesis-related molecules (RUNX2 and OPN) in DOP-ASCs was decreased significantly in comparison with CON-ASCs. JKAMP silencing inhibited the Wnt signaling pathway and reduced the osteogenic ability of CON-ASCs. Overexpression of JKAMP in DOP-ASCs rescued the impaired osteogenic capacity caused by DOP. Moreover, JKAMP in DOP-ASCs contained intragenic DNA hypermethylated regions related to the downregulation of JKAMP expression.ConclusionsIntragenic DNA methylation inhibits the osteogenic ability of DOP-ASCs by suppressing expression of JKAMP and the Wnt signaling pathway. This study shows an epigenetic explanation for the reduced osteogenic ability of DOP-ASCs and provides a potential therapeutic target to prevent and treat osteoporosis.

【 授权许可】

CC BY