title: FFA-ROS-P53-mediated mitochondrial apoptosis contributes to reduction of osteoblastogenesis and bone mass in type 2 diabetes mellitus.
abstract: This study evaluated the association between free fatty acid (FFA), ROS generation, mitochondrial dysfunction and bone mineral density (BMD) in type 2 diabetic patients and investigated the molecular mechanism. db/db and high fat (HF)-fed mice were treated by Etomoxir, an inhibitor of CPT1, MitoQ, and PFT-α, an inhibitor of P53. Bone metabolic factors were assessed and BMSCs were isolated and induced to osteogenic differentiation. FFA, lipid peroxidation and mtDNA copy number were correlated with BMD in T2DM patients. Etomoxir, MitoQ and PFT-α significantly inhibited the decrease of BMD and bone breaking strength in db/db and HF-fed mice and suppressed the reduction of BMSCs-differentiated osteoblasts. Etomoxir and MitoQ, but not PFT-α, inhibited the increase of mitochondrial ROS generation in db/db and HF-fed mice and osteoblasts. In addition, Etomoxir, MitoQ and PFT-α significantly inhibited mitochondrial dysfunction in osteoblasts. Moreover, mitochondrial apoptosis was activated in osteoblasts derived from db/db and HF-fed mice, which was inhibited by Etomoxir, MitoQ and PFT-α. Furthermore, mitochondrial accumulation of P53 recruited Bax and initiated molecular events of apoptotic events. These results demonstrated that fatty acid oxidation resulted in ROS generation, activating P53/Bax-mediated mitochondrial apoptosis, leading to reduction of osteogenic differentiation and bone loss in T2DM.
authors.affiliation: Department of Orthopaedic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Endocrinology, Xi'an NO.1 Hospital, Xi'an 710002, China.
authors.forename: Wang
authors.initials: W
authors.lastname: He
authors.affiliation: Department of Orthopaedic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Liao
authors.affiliation: Jingyue Yang, Department of Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jingyue
authors.initials: J
authors.lastname: Yang
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D052160:Benzothiazoles / Q000494:pharmacology; D015519:Bone Density; D003430:Cross-Sectional Studies; D004272:DNA, Mitochondrial / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology*; D004852:Epoxy Compounds / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D006801:Humans; D015227:Lipid Peroxidation; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D052160:Benzothiazoles; D004272:DNA, Mitochondrial; D004852:Epoxy Compounds; D005230:Fatty Acids, Nonesterified; D009943:Organophosphorus Compounds; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D014451:Ubiquinone; D014050:Toluene; C429014:mitoquinone; C121565:pifithrin; C054207:etomoxir