Irisin Promotes Osteogenesis by Modulating Oxidative Stress and Mitophagy through SIRT3 Signaling under Diabetic Conditions

作者全名："Li, Guangyue; Jian, Zixiang; Wang, He; Xu, Ling; Zhang, Tingwei; Song, Jinlin"

作者地址："[Li, Guangyue; Jian, Zixiang; Wang, He; Xu, Ling; Zhang, Tingwei; Song, Jinlin] Chongqing Key Lab Oral Dis & Biomed Sci, Chongqing, Peoples R China; [Li, Guangyue; Jian, Zixiang; Wang, He; Xu, Ling; Zhang, Tingwei; Song, Jinlin] Chongqing Municipal Key Lab Oral Biomed Engn Highe, Chongqing, Peoples R China; [Li, Guangyue; Jian, Zixiang; Wang, He; Xu, Ling; Zhang, Tingwei; Song, Jinlin] Chongqing Med Univ, Coll Stomatol, Chongqing, Peoples R China"

通信作者："Song, JL (通讯作者)，Chongqing Key Lab Oral Dis & Biomed Sci, Chongqing, Peoples R China.; Song, JL (通讯作者)，Chongqing Municipal Key Lab Oral Biomed Engn Highe, Chongqing, Peoples R China.; Song, JL (通讯作者)，Chongqing Med Univ, Coll Stomatol, Chongqing, Peoples R China."

来源：OXIDATIVE MEDICINE AND CELLULAR LONGEVITY

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000876418600001

JCR分区：Q2

影响因子：7.31

年份：2022

卷号：2022

期号：　

开始页：　

结束页：　

文献类型：Article

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摘要："Advanced glycation end products (AGEs) accumulate in the bone tissue of patients with diabetes mellitus, resulting in oxidative stress, poor bone healing, or regeneration. Irisin, a novel exercise-induced myokine, is involved in the regulation of bone metabolism. However, the effects of irisin on adipose-derived stem cell (ASC) osteogenic differentiation and bone healing under diabetic conditions remain poorly understood. ASCs were obtained from inguinal fat of Sprague-Dawley rats and treated with different concentrations of AGEs and irisin. Cell proliferation, apoptosis, and osteogenic differentiation abilities of ASCs were detected. To explore the regulatory role of sirtuin 3 (SIRT3), ASCs were transfected with lentivirus-mediated SIRT3 overexpression or knockdown vectors. Next, we investigated mitochondrial functions, mitophagy, and mitochondrial biogenesis in different groups. Moreover, SOD2 acetylation and potential signaling pathways were assessed. Additionally, a diabetic rat model was used to evaluate the effect of irisin on bone healing in calvarial critical-sized defects (CSDs) in vivo. Our results showed that irisin incubation mitigated the inhibitory effects of AGEs on ASCs by increasing cell viability and promoting osteogenesis. Moreover, irisin modulated mitochondrial membrane potential, intracellular ROS levels, mitochondrial O-2(center dot-) status, ATP generation, complex I and IV activities, mitophagy, and mitochondrial biogenesis via a SIRT3-mediated pathway under AGEs exposure. Furthermore, in calvarial CSDs of diabetic rats, transplantation of gels encapsulating irisin-pretreated ASCs along with irisin largely enhanced bone healing. These findings suggest that irisin attenuates AGE-induced ASC dysfunction through SIRT3-mediated maintenance of oxidative stress homeostasis and regulation of mitophagy and mitochondrial biogenesis. Thus, our studies shed new light on the role of irisin in promoting the ASC osteogenesis and targeting SIRT3 as a novel therapeutic intervention strategy for bone regeneration under diabetic conditions."

基金机构："National Natural Science Foundation of China [81800938, 81771082, 31971282]; 2019 Chongqing Graduate Tutor Team Construction Project [dstd201903]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (Grant Nos. 81800938, 81771082, and 31971282). This research was also supported by dstd201903 from the 2019 Chongqing Graduate Tutor Team Construction Project."