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

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 inve...

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Autores principales:	Miao Chen, Dian Jing, Rui Ye, Jianru Yi, Zhihe Zhao
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	PPARβ/δ Diabetes mellitus Autophagy Osteogenic differentiation Bone regeneration AMPK/mTOR pathway Medicine (General) R5-920 Biochemistry QD415-436
Acceso en línea:	https://doaj.org/article/9f7f686015c4449295f6eb1cf8ae7855
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spelling	oai:doaj.org-article:9f7f686015c4449295f6eb1cf8ae78552021-11-07T12:07:38ZPPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy10.1186/s13287-021-02628-81757-6512https://doaj.org/article/9f7f686015c4449295f6eb1cf8ae78552021-11-01T00:00:00Zhttps://doi.org/10.1186/s13287-021-02628-8https://doaj.org/toc/1757-6512Abstract 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.Miao ChenDian JingRui YeJianru YiZhihe ZhaoBMCarticlePPARβ/δDiabetes mellitusAutophagyOsteogenic differentiationBone regenerationAMPK/mTOR pathwayMedicine (General)R5-920BiochemistryQD415-436ENStem Cell Research & Therapy, Vol 12, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	PPARβ/δ Diabetes mellitus Autophagy Osteogenic differentiation Bone regeneration AMPK/mTOR pathway Medicine (General) R5-920 Biochemistry QD415-436
spellingShingle	PPARβ/δ Diabetes mellitus Autophagy Osteogenic differentiation Bone regeneration AMPK/mTOR pathway Medicine (General) R5-920 Biochemistry QD415-436 Miao Chen Dian Jing Rui Ye Jianru Yi Zhihe Zhao PPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy
description	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.
format	article
author	Miao Chen Dian Jing Rui Ye Jianru Yi Zhihe Zhao
author_facet	Miao Chen Dian Jing Rui Ye Jianru Yi Zhihe Zhao
author_sort	Miao Chen
title	PPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy
title_short	PPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy
title_full	PPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy
title_fullStr	PPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy
title_full_unstemmed	PPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy
title_sort	pparβ/δ accelerates bone regeneration in diabetic mellitus by enhancing ampk/mtor pathway-mediated autophagy
publisher	BMC
publishDate	2021
url	https://doaj.org/article/9f7f686015c4449295f6eb1cf8ae7855
work_keys_str_mv	AT miaochen pparbdacceleratesboneregenerationindiabeticmellitusbyenhancingampkmtorpathwaymediatedautophagy AT dianjing pparbdacceleratesboneregenerationindiabeticmellitusbyenhancingampkmtorpathwaymediatedautophagy AT ruiye pparbdacceleratesboneregenerationindiabeticmellitusbyenhancingampkmtorpathwaymediatedautophagy AT jianruyi pparbdacceleratesboneregenerationindiabeticmellitusbyenhancingampkmtorpathwaymediatedautophagy AT zhihezhao pparbdacceleratesboneregenerationindiabeticmellitusbyenhancingampkmtorpathwaymediatedautophagy
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PPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy

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