title: Tetramethylpyrazine Protects Against Glucocorticoid-Induced Apoptosis by Promoting Autophagy in Mesenchymal Stem Cells and Improves Bone Mass in Glucocorticoid-Induced Osteoporosis Rats.
abstract: Glucocorticoid-induced osteoporosis (GIOP) is a widespread clinical complication due to the common use of glucocorticoids. Excess glucocorticoids induce apoptosis of bone marrow-derived mesenchymal stem cells (BMSCs), which have been shown to play an increasingly important role in the pathogenesis and therapy of osteoporosis. Tetramethylpyrazine (TMP), an extract from one of the most recognized herbs in traditional Chinese medicine (Chuanxiong), has been reported to have antiapoptotic properties. In this study, we tested whether TMP protects rat BMSCs following exposure to glucocorticoids in vitro and in vivo. We treated BMSCs with different concentrations of TMP (50, 100, or 200 μM) and exposed them to 10-6M dexamethasone (Dex) for 48 h in vitro. Our data showed that TMP inhibited Dex-induced cytotoxicity and protected BMSCs from apoptosis. Interestingly, further results demonstrated that TMP prevented apoptosis in BMSCs by promoting autophagy in an AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) pathway-dependent manner. In addition, calcein fluorescence double labeling and microcomputed tomography scanning indicated that 12 weeks of TMP administration augmented bone formation and protected trabecular bone mass in GIOP rats. We also discovered that first-passage BMSCs isolated from the TMP treatment group had a lower rate of apoptosis and a higher light chain 3 (LC3)-II/LC3-I ratio than the GIOP group. Our findings demonstrate for the first time that TMP can protect BMSCs from exposure to excess glucocorticoids by promoting autophagy through AMPK/mTOR pathway and might be an effective agent for the prevention and treatment of GIOP.
authors.affiliation: 1 Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University , Xi'an, People's Republic of China .
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.affiliation: 1 Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University , Xi'an, People's Republic of China .
authors.forename: Hong-Yang
authors.initials: HY
authors.lastname: Zhang
authors.affiliation: 1 Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University , Xi'an, People's Republic of China .
authors.forename: Bo
authors.initials: B
authors.lastname: Gao
authors.affiliation: 1 Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University , Xi'an, People's Republic of China .
authors.forename: Jun
authors.initials: J
authors.lastname: Shi
authors.affiliation: 1 Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University , Xi'an, People's Republic of China .
authors.forename: Qiang
authors.initials: Q
authors.lastname: Huang
authors.affiliation: 1 Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University , Xi'an, People's Republic of China .
authors.forename: Yue-Hu
authors.initials: YH
authors.lastname: Han
authors.affiliation: 1 Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University , Xi'an, People's Republic of China .
authors.forename: Ya-Qian
authors.initials: YQ
authors.lastname: Hu
authors.affiliation: 1 Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University , Xi'an, People's Republic of China .
authors.forename: Wei-Guang
authors.initials: WG
authors.lastname: Lu
authors.affiliation: 1 Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University , Xi'an, People's Republic of China .
authors.forename: Zhuo-Jie
authors.initials: ZJ
authors.lastname: Zhao
authors.affiliation: 2 Health Science Center, Shenzhen University , Shenzhen, People's Republic of China .
authors.forename: Bao-Hua
authors.initials: BH
authors.lastname: Liu
authors.affiliation: 1 Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University , Xi'an, People's Republic of China .
authors.forename: Qiang
authors.initials: Q
authors.lastname: Jie
authors.affiliation: 1 Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University , Xi'an, People's Republic of China .
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: 1 Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University , Xi'an, People's Republic of China .
authors.forename: Zhuo-Jing
authors.initials: ZJ
authors.lastname: Luo
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology*; D003907:Dexamethasone; D005938:Glucocorticoids / Q000009:adverse effects*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects; D010024:Osteoporosis / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D020011:Protective Agents; D011719:Pyrazines; D003907:Dexamethasone; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C017953:tetramethylpyrazine
keywords: autophagy; bone marrow-derived mesenchymal stem cells; glucocorticoids; osteoporosis; tetramethylpyrazine