title: Metformin protects against apoptosis and senescence in nucleus pulposus cells and ameliorates disc degeneration in vivo.
abstract: Intervertebral disc degeneration (IDD) is a complicated process that involves both cellular apoptosis and senescence. Metformin has been reported to stimulate autophagy, whereas autophagy is shown to protect against apoptosis and senescence. Therefore, we hypothesize that metformin may have therapeutic effect on IDD through autophagy stimulation. The effect of metformin on IDD was investigated both in vitro and in vivo. Our study showed that metformin attenuated cellular apoptosis and senescence induced by tert-butyl hydroperoxide in nucleus pulposus cells. Autophagy, as well as its upstream regulator AMPK, was activated by metformin in nucleus pulposus cells in a dose- and time-dependent manner. Inhibition of autophagy by 3-MA partially abolished the protective effect of metformin against nucleus pulposus cells' apoptosis and senescence, indicating that autophagy was involved in the protective effect of metformin on IDD. In addition, metformin was shown to promote the expression of anabolic genes such as Col2a1 and Acan expression while inhibiting the expression of catabolic genes such as Mmp3 and Adamts5 in nucleus pulposus cells. In vivo study illustrated that metformin treatment could ameliorate IDD in a puncture-induced rat model. Thus, our study showed that metformin could protect nucleus pulposus cells against apoptosis and senescence via autophagy stimulation and ameliorate disc degeneration in vivo, revealing its potential to be a therapeutic agent for IDD.
authors: Department of Orthopaedics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.|Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, Zhejiang Province, China.
authors: Deheng
authors: D
authors: Chen
authors: Department of Orthopaedics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.|Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, Zhejiang Province, China.|Department of Spinal Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
authors: Dongdong
authors: D
authors: Xia
authors: Department of Orthopaedics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.|Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, Zhejiang Province, China.
authors: Zongyou
authors: Z
authors: Pan
authors: Department of Orthopaedics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.|Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, Zhejiang Province, China.
authors: Daoliang
authors: D
authors: Xu
authors: Department of Orthopaedics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.|Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, Zhejiang Province, China.
authors: Yifei
authors: Y
authors: Zhou
authors: Department of Orthopaedics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.|Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, Zhejiang Province, China.
authors: Yaosen
authors: Y
authors: Wu
authors: Department of Orthopaedics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.|Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, Zhejiang Province, China.
authors: Ningyu
authors: N
authors: Cai
authors: Department of Orthopaedics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.|Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, Zhejiang Province, China.
authors: Qian
authors: Q
authors: Tang
authors: Department of Orthopaedics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.|Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, Zhejiang Province, China.
authors: Chenggui
authors: C
authors: Wang
authors: Department of Spinal Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
authors: Meijun
authors: M
authors: Yan
authors: Department of Spinal Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
authors: Jing Jie
authors: JJ
authors: Zhang
authors: Department of Orthopaedics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.|Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, Zhejiang Province, China.
authors: Kailiang
authors: K
authors: Zhou
authors: Department of Orthopaedics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.|Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, Zhejiang Province, China.
authors: Quan
authors: Q
authors: Wang
authors: Department of Orthopaedics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.|Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, Zhejiang Province, China.
authors: Yongzeng
authors: Y
authors: Feng
authors: Department of Orthopaedics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.|Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, Zhejiang Province, China.
authors: Xiangyang
authors: X
authors: Wang
authors: Department of Orthopaedics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.|Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, Zhejiang Province, China.
authors: Huazi
authors: H
authors: Xu
authors: Department of Orthopaedics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.|Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, Zhejiang Province, China.|Chinese Orthopaedic Regenerative Medicine Society, Hangzhou, China.
authors: Xiaolei
authors: X
authors: Zhang
authors: Department of Orthopaedics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.|Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, Zhejiang Province, China.
authors: Naifeng
authors: N
authors: Tian
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001343:Autophagy / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D055959:Intervertebral Disc Degeneration / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D008297:Male; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000070614:Nucleus Pulposus / Q000187:drug effects / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D020122:tert-Butylhydroperoxide
chemical_list: D018696:Neuroprotective Agents; D034741:RNA, Small Interfering; C025946:3-methyladenine; D008687:Metformin; D020122:tert-Butylhydroperoxide; D000263:Adenylate Kinase; D000225:Adenine