miR-221-3p and miR-222-3p downregulation promoted osteogenic differentiation of bone marrow mesenchyme stem cells through IGF-1/ERK pathway under high glucose condition

Abstract Background Progressive population aging has contributed to the increased global prevalence of diabetes and osteoporosis. Inhibition of osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) by hyperglycemia is a potential pathogenetic mechanism of osteoporosis in diabetic patients. Uncarboxylated osteocalcin (GluOC), a protein secreted by mature osteoblasts, regulates bone development as well as glucose and lipid metabolism. In our previous studies, GluOC was shown to promote osteoblastic differentiation of BMSCs; however, the underlying mechanisms are not well characterized. Tumor protein 63 (TP63), as a transcription factor, is closely related to bone development and glucose metabolism. Results In this study, we verified that high glucose suppressed osteogenesis and upregulated adipogenesis in BMSCs, while GluOC alleviated this phenomenon. In addition, high glucose enhanced TP63 expression while GluOC diminished it. Knock-down of TP63 by siRNA transfection restored the inhibitory effect of high glucose on osteogenic differentiation. Furthermore, we detected the downstream signaling pathway PTEN/Akt/GSK3β. We found that diminishing TP63 decreased PTEN expression and promoted the phosphorylation of Akt and GSK3β. We then applied the activator and inhibitor of Akt, and concluded that PTEN/Akt/GSK3β participated in regulating the differentiation of BMSCs. Conclusions Our results indicate that GluOC reduces the inhibitory effect of high glucose on osteoblast differentiation by regulating the TP63/PTEN/Akt/GSK3β pathway. TP63 is a potential novel target for the prevention and treatment of diabetic osteoporosis.

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Upregulated miR-9-5p inhibits osteogenic differentiation of bone marrow mesenchymal stem cells under high glucose treatment

Journal of Bone and Mineral Metabolism ◽

10.1007/s00774-021-01280-9 ◽

2021 ◽

Author(s):

Chuanmei He ◽

Mingming Liu ◽

Qun Ding ◽

Fumeng Yang ◽

Tongdao Xu

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Osteogenic Differentiation ◽

High Glucose ◽

Marrow Mesenchymal Stem Cells ◽

Glucose Treatment

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Effect of metformin and celecoxib on cytotoxicity and release of GDF-15 from human mesenchymal stem cells in high glucose condition

Cell Biochemistry and Function ◽

10.1002/cbf.3289 ◽

2017 ◽

Vol 35 (7) ◽

pp. 407-413 ◽

Cited By ~ 3

Author(s):

Elaheh Zafarvahedian ◽

Azam Roohi ◽

Mohammad Reza Sepand ◽

Seyed Nasser Ostad ◽

Mohammad Hossein Ghahremani

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

High Glucose ◽

Human Mesenchymal Stem Cells ◽

High Glucose Condition ◽

Glucose Condition

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PPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02628-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Miao Chen ◽

Dian Jing ◽

Rui Ye ◽

Jianru Yi ◽

Zhihe Zhao

Keyword(s):

Bone Regeneration ◽

Osteogenic Differentiation ◽

Bone Healing ◽

High Glucose ◽

Diabetic Rats ◽

Diabetic Patients ◽

Regulatory Effect ◽

Compound C ◽

High Glucose Condition ◽

Glucose Condition

Abstract Background Diabetic patients are more vulnerable to skeletal complications. Peroxisome proliferators-activated receptor (PPAR) β/δ has a positive regulatory effect on bone turnover under physiologic glucose concentration; however, the regulatory effect in diabetes mellitus has not been investigated yet. Herein, we explored the effects of PPARβ/δ agonist on the regeneration of diabetic bone defects and the osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs) under a pathological high-glucose condition. Methods We detected the effect of PPARβ/δ agonist on osteogenic differentiation of rBMSCs in vitro and investigated the bone healing process in diabetic rats after PPARβ/δ agonist treatment in vivo. RNA sequencing was performed to detect the differentially expressed genes and enriched pathways. Western blot was performed to detect the autophagy-related protein level. Laser confocal microscope (LSCM) and transmission electron microscope (TEM) were used to observe the formation of autophagosomes. Results Our results demonstrated that the activation of PPARβ/δ can improve the osteogenic differentiation of rBMSCs in high-glucose condition and promote the bone regeneration of calvarial defects in diabetic rats, while the inhibition of PPARβ/δ alleviated the osteogenic differentiation of rBMSCs. Mechanistically, the activation of PPARβ/δ up-regulates AMPK phosphorylation, yielding mTOR suppression and resulting in enhanced autophagy activity, which further promotes the osteogenic differentiation of rBMSCs in high-glucose condition. The addition of AMPK inhibitor Compound C or autophagy inhibitor 3-MA inhibited the osteogenesis of rBMSCs in high-glucose condition, suggesting that PPARβ/δ agonist promotes osteogenic differentiation of rBMSCs through AMPK/mTOR-regulated autophagy. Conclusion In conclusion, our study demonstrates the potential role of PPARβ/δ as a molecular target for the treatment of impaired bone quality and delayed bone healing in diabetic patients for the first time.

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Astragaloside IV attenuates Toll-like receptor 4 expression via NF-κB pathway under high glucose condition in mesenchymal stem cells

European Journal of Pharmacology ◽

10.1016/j.ejphar.2012.09.033 ◽

2012 ◽

Vol 696 (1-3) ◽

pp. 203-209 ◽

Cited By ~ 15

Author(s):

Mincai Li ◽

Liangzu Yu ◽

Tonghui She ◽

Yapin Gan ◽

Fuxin Liu ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

High Glucose ◽

Toll Like Receptor ◽

Astragaloside Iv ◽

Toll Like Receptor 4 ◽

High Glucose Condition ◽

Glucose Condition

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High glucose inhibits osteogenic differentiation of bone marrow mesenchymal stem cells via regulating miR-493-5p/ZEB2 signalling

The Journal of Biochemistry ◽

10.1093/jb/mvaa011 ◽

2020 ◽

Vol 167 (6) ◽

pp. 613-621

Author(s):

Zhongshu Zhai ◽

Wanhong Chen ◽

Qiaosheng Hu ◽

Xin Wang ◽

Qing Zhao ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Osteogenic Differentiation ◽

High Glucose ◽

Underlying Mechanism ◽

Luciferase Assay ◽

Downstream Target ◽

Marrow Mesenchymal Stem Cells ◽

Diabetic Osteoporosis

Abstract Diabetic osteoporosis (DOP) is attributed to the aberrant physiological function of bone marrow mesenchymal stem cells (BMSCs) under high glucose (HG) environment. MicroRNAs (miRNAs) are involved in the pathological processes of DOP. We aimed to explore the underlying mechanism of miRNA in DOP. BMSCs were cultured in osteogenic medium with HG to induce osteogenic differentiation, and the interaction between miR-493-5p and ZEB2 was assessed by luciferase assay. Herein, we found miR-493-5p is gradually reduced during osteogenic differentiation in BMSCs. HG treatment inhibits osteogenic differentiation and induces an up-regulation of miR-493-5p leading to reduced level of its downstream target ZEB2. Inhibition of miR-493-5p attenuates HG-induced osteogenic differentiation defects by upregulation of ZEB2. Mechanistically, miR-493-5p/ZEB2 signalling mediates HG-inhibited osteogenic differentiation by inactivation of Wnt/β-catenin signalling. More importantly, knockdown of miR-493-5p therapeutically alleviated the DOP condition in mice. HG prevents BMSCs osteogenic differentiation via up-regulation of miR-493-5p, which results in reduced level of ZEB2 by directly targeting its 3′-untranslated region of mRNA. Thus, miR-493-5p/ZEB2 is a potential therapeutic target and provides novel strategy for the treatment and management of DOP.

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