Resveratrol counteracts bone loss via mitofilin-mediated osteogenic improvement of mesenchymal stem cells in senescence-accelerated mice

被引:116
作者
Lv, Ya-Jie [1 ,4 ]
Yang, Yi [1 ,3 ]
Sui, Bing-Dong [1 ,2 ]
Hu, Cheng-Hu [1 ,2 ]
Zhao, Pan [1 ,2 ]
Liao, Li [1 ,2 ]
Chen, Ji [1 ]
Zhang, Li-Qiang [1 ,2 ]
Yang, Tong-Tao [5 ]
Zhang, Shao-Feng [3 ]
Jin, Yan [1 ,2 ]
机构
[1] Fourth Mil Med Univ, Sch Stomatol, Ctr Tissue Engn, State Key Lab Mil Stomatol, 145 West Changle Rd, Xian 710032, Shaanxi, Peoples R China
[2] Xian Inst Tissue Engn & Regenerat Med, Xian 710032, Shaanxi, Peoples R China
[3] Fourth Mil Med Univ, Sch Stomatol, Dept Prosthodont, State Key Lab Mil Stomatol, 145 West Changle Rd, Xian 710032, Shaanxi, Peoples R China
[4] Fourth Mil Med Univ, Tangdu Hosp, Dept Dermatol, Xian 710069, Shannxi, Peoples R China
[5] Fourth Mil Med Univ, Tangdu Hosp, Dept Orthopaed, Xian 710069, Shannxi, Peoples R China
来源
THERANOSTICS | 2018年 / 8卷 / 09期
基金
中国国家自然科学基金;
关键词
resveratrol; osteoporosis; mesenchymal stem cells; senescence-accelerated mice; osteogenesis; Mitofilin/IMMT/Mic60; MITOCHONDRIAL TRANSCRIPTION FACTOR; ACTIVATED PROTEIN-KINASE; MURINE MODEL; LIFE-SPAN; IN-VITRO; IMPAIRED OSTEOBLASTOGENESIS; ANTIAGING PHARMACOLOGY; PERIODONTAL-LIGAMENT; ADIPOCYTE FORMATION; CRISTAE MORPHOLOGY;
D O I
10.7150/thno.23620
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Rational: Senescence of mesenchymal stem cells (MSCs) and the related functional decline of osteogenesis have emerged as the critical pathogenesis of osteoporosis in aging. Resveratrol (RESV), a small molecular compound that safely mimics the effects of dietary restriction, has been well documented to extend lifespan in lower organisms and improve health in aging rodents. However, whether RESV promotes function of senescent stem cells in alleviating age-related phenotypes remains largely unknown. Here, we intend to investigate whether RESV counteracts senescence-associated bone loss via osteogenic improvement of MSCs and the underlying mechanism. Methods: MSCs derived from bone marrow (BMMSCs) and the bone-specific, senescence-accelerated, osteoblastogenesis/osteogenesis-defective mice (the SAMP6 strain) were used as experimental models. In vivo application of RESV was performed at 100 mg/kg intraperitoneally once every other day for 2 months, and in vitro application of RESV was performed at 10 mu M. Bone mass, bone formation rates and osteogenic differentiation of BMMSCs were primarily evaluated. Metabolic statuses of BMMSCs and the mitochondrial activity, transcription and morphology were also examined. Mitofilin expression was assessed at both mRNA and protein levels, and short hairpin RNA (shRNA)-based gene knockdown was applied for mechanistic experiments. Results: Chronic intermittent application of RESV enhances bone formation and counteracts accelerated bone loss, with RESV improving osteogenic differentiation of senescent BMMSCs. Furthermore, in rescuing osteogenic decline under BMMSC senescence, RESV restores cellular metabolism through mitochondrial functional recovery via facilitating mitochondrial autonomous gene transcription. Molecularly, in alleviating senescence-associated mitochondrial disorders of BMMSCs, particularly the mitochondrial morphological alterations, RESV upregulates Mitofilin, also known as inner membrane protein of mitochondria (Immt) or Mic60, which is the core component of the mitochondrial contact site and cristae organizing system (MICOS). Moreover, Mitofilin is revealed to be indispensable for mitochondrial homeostasis and osteogenesis of BMMSCs, and that insufficiency of Mitofilin leads to BMMSC senescence and bone loss. More importantly, Mitofilin mediates resveratrol-induced mitochondrial and osteogenic improvements of BMMSCs in senescence. Conclusion: Our findings uncover osteogenic functional improvements of senescent MSCs as critical impacts in anti-osteoporotic practice of RESV, and unravel Mitofilin as a novel mechanism mediating RESV promotion on mitochondrial function in stem cell senescence.
引用
收藏
页码:2387 / 2406
页数:20
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